The Department of Biosciences and Nutrition

Transcription

The Department of
Biosciences and Nutrition
Scientific Report 2010-2012
Contents
Introduction
7
Roger Strömberg: Nucleic acids and peptides in biotechnology and therapy27
Research groups
Staffan Strömblad: Cell biology of cancer 28
Thomas Bürglin: Studying how cell specialization is regulated 8
Peter Swoboda: From the basic biology of cilia to ciliopathy disease states in humans29
Karin Dahlman-Wright: ESR - estrogen signaling research group 9
Jussi Taipale: Systems biology group30
Mauro D'Amato: Molecular genetics of gastrointestinal disease10
Rune Toftgård: Hedgehog signalling, tissue stem cells and cancer development31
Carsten Daub: Clinical transcriptomics11
Eckardt Treuter: Epigenomic control of metaflammation by nuclear receptor-coregulator pathways32
Karl Ekwall: Epigenetics, chromatin remodeling and cancer12
Agneta Yngve: Public health nutrition33
Maria Eriksson: Searching for genetic mechanisms that affect aging13
Core facilities Henrik Garoff: Activation of HIV-1 and murine leukemia virus 14
Bioinformatics and expression analysis, BEA 34
Jan-Åke Gustafsson: Nuclear receptors in health and disease 15
Center for high resolution electron microscopy, EM
35
Hans Hebert: Cryo electron microscopy of membrane proteins and biomolecular assemblies16
The live cell imaging unit, LCI
36
Luca Jovine: Structural studies of egg-sperm interaction and human hedgehog signaling proteins17
Karolinska high throughput center, KHTC
37
Maria Kasper: Stem cell dynamics in skin - from homeostasis to cancer18
Examples of high impact publications 38
Juha Kere: Molecular genetics and biology of complex diseases19
Dissertations 2010-201240
Marie Löf: Early-life factors important for childhood obesity: observational and interventional studies
Undergraduate teaching 20
42
Lennart Möller: Analytical toxicology and clinical applications21
Networks 44
Lennart Nilsson: Simulating the behavior of proteins and nucleic acids22
Awards
45
Sam Okret: Effects of glucocorticoids and estrogens on cells and functions of the immune systems23
The department in brief
46
Joseph Rafter: Host - microbe intearctions24
Organization 48
Michael Sjöström: Childhood factors and cardiovascular health 25
Contact
49
Dan Segerbäck: Monitoring human exposure to ultraviolet radiation26
4
5
Introduction
Welcome to the Department of Biosciences and Nutrition (BioNut) at the Karolinska Institutet Campus Huddinge. In your
hands you hold our Scientific Report for the last three years, 2010-2012.
The front page is illustrating the most critical asset of our department, the people, past and present, who all contributed and
contribute to make the department what it is: An academic environment where the international dimension and diversity, with
students and researchers from all over the globe, enrich the scientific, educational and social environment.
Our vision is to conduct biomedical research at the international research front that attracts world-class individuals, coupled
to a quality-assured academic education, and to be an attractive partner for the health care system, the industrial sector and
leading research centers.
The strategy aims to provide a high quality and comprehensive unit for preclinical medical research and related education at
the KI Campus Huddinge with multifaceted and productive collaborations with Karolinska University Hospital and the Royal
Institute of Technology (KTH), among others.
With a translational ambition, our goal is to provide a consolidated bench component of a bed to bench translation with close
multiple and diverse collaborations with clinical colleagues.
The core activities of our department are conducted within the context of approximately 25 research groups, the activities and
achievements of which are described on the following pages. These groups represent a broad repertoire of basic science, however, some themes are apparent such as genomics in a broad perspective, structural biology and nutrition. From a therapeutic
area perspective, cancer and metabolic disease are areas approached by many groups. Educational activities are mainly in areas
of biomedicine and nutrition, well aligned with the research focuses of the department. The department also houses four core
facilities three of which, the Bioinformatics and Expression Analysis, BEA, the Center for High Resolution Electron Microscopy,
EM and the Karolinska High Throughput Center, KHTC , have a nationwide ambition. The activities of our core facilities are
well in line with the scientific focuses of our department. Importantly, our core activities rely on the professional assistance of
our support functions, including functions for laboratory service, human resources, economy, research support and IT.
Looking back at the last three years, every day was a scientific and educational experience. Rather than addressing any specific
achievement, I leave for you the reader, to choose your own highlights from what is provided on the following pages.
Looking into the future, I am sure it will be just as unexpected, exciting and challenging as the past. We, the people that constitutes the Department of Biosciences and Nutrition, with the competences and experiences that we represent, are now ready to
step into the future to continue to address prioritized biomedical problems and improve human health.
Finally, I like to thank Marie Franzén and Camilla Wernersson, their hard work, organizational skills
and creativity have been instrumental to complete this scientific report.
Karin Dahlman Wright
7
Studying how cell
specialization is regulated
Tomas Bürglin
+46 8 585 837 33
[email protected]
ki.se/bionut/burglin
Selected publications
Tammimies, K., Vitezic, M., Matsson, H., Le
Guyader, S., Bürglin, T.R., Öhman, T., Strömblad, S., Daub, C.O., Nyman, T.A., Kere, J., and
Tapia-Páez, I. Molecular networks of DYX1C1
gene show connection to neuronal migration
genes and cyoskeletal proteins. Biol. Psychiatry, 73(6):583-90.
Bürglin, T.R. (2011) Homeodomain subtypes
and functional diversity. Subcell. Biochem.
52:95-122.
Ohkura, K., Bürglin T.R. (2011) Dye-filling of
the amphid sheath glia: implications for the
functional relationship between sensory neurons
and glia in Caenorhabditis elegans. Biochem
Biophys Res Commun. 406:188-193.
Caenorhabditis elegans has several genes related
to the signaling molecule Hedgehog, a key
molecule in carcinogenesis. We showed that
the hedgehog-related gene wrt-6 is expressed in
the amphid and phasmid socket cells of sensory
neurons, and found that wrt-6 mutants are lipid
dye-filling defective, and have reduced dauer
formation, which is induced by lipid-type pheromones. We conclude that WRT-6 is required
for transporting large lipophilic molecules to
sensory cilia.
Hedgehog-related genes in development
We are interested in how cell types are specified
during development. Using our 4D imaging
system, Endrov, we analyzed the promoter region of the homeodomain transcription factor
ceh-5. During embryogenesis, ceh-5 is asymmetrically expressed in two bilaterally symmetric groups of cells. We have shown that an
E-box motif about 70 bp upstream of the ceh-5
ATG is required for this expression, and we
have identified several basic helix-loop-helix
transcription factors that are involved (HLH-2,
CND-1 and NGN-1). Our current model suggests that two different types of heterodimeric
complexes are formed by HLH-2/CND-1 and
HLH-2/NGN-1, respectively, to achieve the
asymmetric expression.
Tracking transcription factors during development using a new imaging framework
The Endrov imaging framework (www.
endrov.net) has been further developed. Its
key strengths are handling of large (> 100 Gb)
N-dimensional data (e.g., multi-channel, multiposition, multi-spectral), making it suitable
for a wide array of tasks, e.g., 3D time-lapse
recordings, systems microscopy, lineaging and
4D modeling of the data.
ESR – estrogen signaling
research group
The overall goal is the development of novel therapeutic strategies targeting estrogen signaling
in metabolic disease, particularly type 2 diabetes (T2D) and breast cancer. There is substantial evidence for the involvement of estrogen
signaling and estrogen receptors (ERs) in T2D
combined with a great unmet medical need for
this disease. Estrogen signaling promotes breast
cancer growth and ER antagonists represent
first line therapy for ER positive breast cancer.
However, all tumors do not respond to this therapy and additionally many tumors eventually
acquire ER antagonist resistance supporting a
need to develop novel therapeutic strategies.
ERα knock-out (KO) mice are obese and
display insulin resistance; however, the target
tissues responsible for these effects remain elusive. Tissue-selective KO animals are well posed to address this issue and we have generated
mice with ERα KO in hepatocytes, adipocytes
and pancreatic β-cells. These studies revealed
that hepatocyte-selective ERα ablation does
not recapitulate the T2D phenotype. We are
exploring several avenues to modulate estrogen
signaling in breast cancer cells.
We have demonstrated that members of a
family of E3 ubiquitin ligases can modulate
ERα levels and cell proliferation and suggest
that these proteins could constitute novel drug
targets. The extensive cross talk between estrogen signaling and AP-1 signaling that we have
described indicates a potential of modulators of
AP-1 family in management of breast cancer.
Xue-Franzén, Y., Johnsson, A., Brodin, D.,
Henriksson, J., Bürglin, T.R., Wright, A.P. ,
(2010) Genome-wide characterisation of the
Gcn5 histone acetyltransferase in budding yeast
during stress adaptation reveals evolutionarily
conserved and diverged roles. BMC Genomics
11:200.
Gustafsson Sheppard, N., Heldring, N. and
Dahlman-Wright, K. (2012) Estrogen receptoralpha, RBCK1 and Protein Kinase C beta1 cooperate to regulate Estrogen Receptor-alpha gene
expression. J Mol Endocrinol. 49(3):277-87.
Dahlman-Wright, K., Qiao Y., Jonsson, P., Gustafsson, J-A., Williams, C. and Zhao, C. (2012)
Interplay between AP-1 and estrogen receptor
in regulating gene expression and proliferation
networks in breast cancer cells. Carcinogenesis
33(9):1684-91.
Gustafsson N, Zhao C, Gustafsson JA and
Dahlman-Wright K. (2010) RBCK1 drives breast
cancer cell proliferation by promoting transcription of estrogen receptor α and cyclin B1.
Cancer Research 70(3):1265-74.
Zhao, C., Gao, H., Liu, Y., Papoutsi, Z., Jaffrey, S.,
Gustafsson J.-Å. and Dahlman-Wright K. (2010)
Genome-wide mapping of estrogen receptorbeta-binding regions reveals extensive cross-talk with transcription factor activator
protein-1. Cancer Research 70(12):5174-83.
Tong, Y.G., Bürglin, T.R. (2010) Conditions for
dye-filling of sensory neurons in Caenorhabditis
elegans. J Neurosci Methods 188:58-61.
Moutsatsou P., Papoutsi Z., Kassi E., Heldring
N., Zhao C., Tsiapara A., Melliou E., Chrousos
GP., Chinou I., Karshikoff A., Nilsson L. and
Dahlman-Wright K. (2010) Fatty acids derived from royal jelly are modulators of estrogen
receptor functions. PLoS ONE 5(12):e 15594.
Group members
Johan Dethlefsen
Umesh Gangishetti
Yong-Guang Tong
Johan Henriksson
Kiyotaka Ohkura
Lois Tang
Model of the C. elegans embryo at the 24-cell stage, lineaged, reconstructed, and modeled using our
open-source software and imaging framework Endrov. Gut blast cells (stem cells) are colored green, predominatly muscle precursors are yellow and blue, and predominantly ectodermal and neuronal precursors
are shades of red and purple. The germ line is descendant from P3’.
8
Karin Dahlman Wright
+46 8 524 810 89
+46 707 266 541
[email protected]
ki.se/bionut/karindahlmanwright
The group is approaching the molecular mechanism of estrogen signaling in metabolic disease and breast
cancer combining phenotypic and functional genomics data with the ultimate goal to derive novel to
identify novel diagnostic criteria and drug targets.
Group members
Gábor Borbely
Karin Dahlman-Wright
Hui Gao
Nina Gustafsson Sheppard
Lars-Arne Haldosén
Malin Hedengran-Faulds
Min Jia
Amirhossein Kharman Biz
Milica Putnik
Yichun Qiao
Indranil Sinha
Li Xu
Chunyan Zhao
Jian Zhu
9
Mauro D'Amato
+46 8 524 810 46
+46 704 355 514
[email protected]
ki.se/bionut/damato
Jostins L, et al. (2012) Host-microbe interactions
have shaped the genetic architecture of inflammatory bowel disease. Nature 491:119-24.
Rivas MA, et al. (2011) Deep resequencing of
GWAS loci identifies independent rare variants
associated with inflammatory bowel disease.
Nat Genet 43:1066-73.
Zucchelli M, et al. (2011) Association of
TNFSF15 polymorphism with susceptibility to
irritable bowel syndrome. Gut 60:1671-7
Anderson CA, et al. (2011) Meta-analysis
identifies 31 additional ulcerative colitis risk loci,
increasing the number of confirmed associations
to 49. Nat Genet 43:246-52.
Molecular genetics of
gastrointestinal disease
Clinical transcriptomics
The elucidation of the genetic mechanisms
leading to gastrointestinal disease represents
our main scientific interest. We focus primarily on inflammatory bowel disease (IBD)
and irritable bowel syndrome (IBS). These are
incurable conditions affecting respectively 1%
and 15% of the general population, and great is
therefore the need to translate genetic findings
into novel therapeutic strategies. We strive to
identify risk genes and their causative variants
by applying genetic, bioinformatic and functional genomic approaches.
High-throughput technologies developed in
the recent years hold great potential for the
application to medical questions, however the
complexity especially in data handling and
analysis aspects, poses a major challenge for
taking advantage of their fullest potential in the
medical and clinical context.
Inflammatory bowel disease (IBD)
Crohn’s disease (CD) and ulcerative colitis
(UC), the 2 major forms of IBD, show a strong
genetic component, and we have contributed
recent breakthrough discoveries within the frame of large international consortia. While 163
IBD risk loci have been already discovered, our
current challenge is to exploit this information
for the identification of novel diagnostic and/
or therapeutic targets, and for the delineation
of genotype-based strategies to personalized
medicine (www.ibdgenetics.org).
Irritable bowel syndrome (IBS)
A heritable component of IBS is suspected,
though few IBS risk genes have been proposed,
which must be seen as non validated hits rather
than true predisposing factors. One important
exception may be TNFSF15, which we first described in IBS and has now been confirmed in
several independent studies. We are expanding
the breadth of our research in IBS by undertaking whole-genome analyses on large cohorts
from several research groups around the world
(www.bellygenes.org).
Functional dysregulation in diseases
Our interests focus on the understanding of the
molecular basis of diseases through translational research, specifically, but not exclusively,
related to inflammation. The key aspects of
our work include genome-wide gene expression analysis from human patient samples
employing technologies such as RNA-Seq, Cap
Analysis of Gene Expression (CAGE) or small
RNA sequencing. Our analysis goes beyond
differentially expressed genes and identifies
a variety of candidate elements responsible
for the observed expression differences in the
disease patients and the associated clinical
phenotypes. Application of sequencing technology to the transcriptome previously has been
utilized to uncover a range of regulatory elements and mechanisms, including regulation
through transcription factors (TFs), nearby but
distinct alternative promoters resulting in the
same protein but employing different sets of
regulatory TFs, expression of anti-sense RNA
to modulate the sense-RNA and the regulatory
role of expressed repeat elements and miRNAs.
Subsequent functional validation studies confirm the suggested regulatory relationships.
10
Arner E, Mejhert N, Kulyté A, Balwierz PJ,
Pachkov M, Cormont M, Lorente-Cebrián S,
Ehrlund A, Laurencikiene J, Hedén P, DahlmanWright K, Tanti JF, Hayashizaki Y, Rydén M,
Dahlman I, van Nimwegen E, Daub CO, Arner
P. (2012) Adipose tissue microRNAs as regulators
of CCL2 production in human obesity. Diabetes
61(8):1986-93.
Vitezic M, Lassmann T, Forrest AR, Suzuki M,
Tomaru Y, Kawai J, Carninci P, Suzuki H, Hayashizaki Y, Daub CO. (2010) Building promoter
aware transcriptional regulatory networks using
siRNA perturbation and deepCAGE. Nucleic
Acids Res. 38(22):8141-8.
Burroughs AM, Ando Y, de Hoon MJ, Tomaru Y,
Nishibu T, Ukekawa R, Funakoshi T, Kurokawa
T, Suzuki H, Hayashizaki Y, Daub CO. (2010)
A comprehensive survey of 3' animal miRNA
modification events and a possible role for 3'
adenylation in modulating miRNA targeting
effectiveness. Genome Res. (10):1398-410.
Artwork by Bang Wong, Broad Institute.
Franke A, et al. (2010) Genome-wide meta-analysis increases to 71 the number of confirmed
Crohn’s disease susceptibility loci. Nat Genet
42:1118-25.
Group members
Ghazaleh Assadi
Francesca Bresso
Lina Cordeddu
Elisabeth Dungner
Ling Li
Evangelia Papadaki
Carsten Daub
+46 8 524 812 24
+46 722 506 890
[email protected]
ki.se/bionut/daub
Group members
Olga Hrydziuszko
Amitha Raman
Nancy Yu
Frequent discussions in the group as well as with the clinical collaborators are essential components of the
research process.
11
Karl Ekwall
+46 8 524 810 39
[email protected]
ki.se/bionut/ekwall
Pointner J, Persson J, Prasad P, Norman-Axelsson U, Strålfors A, Khorosjutina O, Krietenstein
N, Svensson JP, Ekwall K, Korber P. (2012)
CHD1 remodelers regulate nucleosomes spacing
in vitro and align nuclosomal arrays over gene
coding regions in S. pombe. EMBO J. 31:43884403.
Epigenetics, chromatin
remodeling and cancer
Searching for genetic
mechanisms that affect aging
Epigenetics is the study of heritable changes
for example chromosomal states, which are not
associated with changes in the DNA sequence.
The Ekwall group is taking a holistic approach
towards understanding epigenetic regulation, unravelling mechanisms at work both in
centromeres and gene regulation. The group
is using a variety of approaches including
genome-wide 'epigenomics', cell biology and
biochemistry to address important questions
about epigenetic regulatory mechanisms such
as histone modification, nucleosome remodel-
Genetic mechanisms that affect physiological
aging are of high interest to society, yet not well
understood. The Eriksson research group uses
the Hutchinson-Gilford progeria syndrome, or
progeria, as a model for their studies on aging.
Most cases of progeria are caused by mutations in the LMNA gene. Children affected by
progeria are normal at birth but during their
first years of life they start developing multiple
symptoms of premature aging - including loss
of subcutaneous fat, and hair, reduced bone mineral density and osteoporosis. Most children
die in their early teens from complications of
cardio-vascular disease, atherosclerosis.
ling and histone variant function. Translational
medicine aspects of this research are exploited
mainly in the cancer and cell differentiation
areas (epigenetic programming). The group
also recently initiated projects on chromatin
and DNA repair. Currently there are four
main projects in focus; Centromere function
and gene regulation; Chromatin remodeling
factors and nuclear organization; Dissecting the
epigenome in normal human blood cells and
in Acute Myeloid Leukemia (AML); and DNA
damage and chromatin.
Steglich B, Filion G, van Steensel B, Ekwall K.
(2012) The inner nuclear membrane proteins
Man1 and Ima1 link to two different types of
chromatin at the nuclear periphery in S. pombe.
Nucleus 3(1):77-87.
Models of premature aging
The LMNA gene codes for the A-type lamins
which are major proteins of the nuclear lamina.
The lamina plays significant roles in replication, transcription, cell division, and chromatin
organization. The Eriksson research group use
tissue-specific transgenic mice with expression
Sadeghi L, Bonilla C, Strålfors A, Ekwall K,
Svensson JP. (2011) "Podbat: A Novel Genomic
Tool Reveals Swr1-independent H2A.Z Incorporation at Gene Coding Sequences Through
Epigenetic Meta Analysis". PLoS Comput Biol.
7(8): e1002163.
of the most common progeria mutation in skin,
aorta, and bone to form models for common
diseases with aging. Recent published results
from the group showed premature senescence,
increased inflammation, early reduction in the
pool of adult stem cells and impaired wound
healing as a consequence from the expression of the progeria mutation in postnatal
epidermis. Expression of the progeria mutation in the bone results in a severe phenotype
characterized by loss of osteocytes, increased
inflammation, and impaired bone mineralization. Further analysis showed DNA damage
and impaired wnt signaling. In addition, the
phenotype shows similarities to reported
bone abnormalities in aging mice, including
distorted organization, and a hypo-cellular
bone marrow with prominent white adipocytes.
Ongoing studies include the analysis of RNA
splicing and intra-individual somatic genetic
variation acquired during aging.
12
Michelle Rönnerblad
Laia Sadeghi
Lee Siggens
Agata Smialowska
Babett Steglich
Annelie Strålfors
Peter Svensson
Schmidt E, Nilsson O, Koskela A, Tuukkanen J,
Ohlsson C, Rozell B, Eriksson M. (2012) Expression of the Hutchinson-Gilford progeria mutation during osteoblast development results in
loss of osteocytes, irregular mineralization, and
poor biomechanical properties. J Biol Chem.
287(40):33512-22.
Rodriguez S, Eriksson M. (2011) Low and High
Expressing Alleles of the LMNA Gene: Implications for Laminopathy Disease Development.
PLoS ONE, (9):e25472.
Schmidt E, Eriksson M. A (2011) previously
functional tetracycline-regulated transactivator
fails to target gene expression to the bone. BMC
Res Notes. 2011;4:282.
Rodriguez S, Eriksson M. (2010) Evidence for
the involvement of lamins in aging. Curr Aging
Sci. 2010;3:81-89.
Illustration by Andreas Olofsson
Group members
Carolina Bonilla
Wenbo Dong
Olga Khorosjutina
Andreas Lennartsson
Victoria Menéndez Benito
Ulrika Norman-Axelsson
Jenna Persson
Punit Prasad
Rosengardten Y, McKenna T, Grochová D,
Eriksson M. (2011) Stem cell depletion in
Hutchinson-Gilford progeria syndrome. Aging
Cell 10(6):1011-20.
Strålfors A., J. Walfridsson, H. Bhuiyan, and K.
Ekwall. (2011) ‘The FUN30 Chromatin Remodeler, Fft3, Insulates Centromeric and Subtelomeric
Chromatin Domains from Euchromatin’ PLoS
Genetics 7(3): e1001334.
Choi ES, Stralfors A, Castillo AG, Durand-Dubief M, Ekwall K, Allshire RC. (2011) "Identification of non-coding transcripts from within
CENP-A chromatin at fission yeast centromeres."
J Biol Chem. 286(26):23600-7.
Maria Eriksson
+46 8 524 810 48
[email protected]
ki.se/bionut/eriksson
Part of a chromosome with the DNA double helix organized into a more compact structure by formation
of nucleosomes (round spheres). Each nucleosomes contains histone proteins and 146 base-pairs of DNA.
Immunofluorescence with antibodies for the tight
junction protein Occludin antibody in green, human
lamin A/C in pink and DRAQ5 in blue. Dorsal skin
sections were taken from a postnatal day 5 progeriod
animal. Although the tight junction layer is functional in the progeriod animals as in the wild-type, the
larger exposure area of nucleated cells outside of the
tight junction layer, due to epidermal hyperplasia,
causes a greater rate of dehydration in progeriod
compared to wild-type animals.
Group members
Jean-Ha Baek
Tomás McKenna
Hasina Nasser
Sofia Rodriguez
Ylva Rosengardten
Eva Schmidt
Charlotte Strandgren
Nikenza Viceconte
13
Henrik Garoff
+46 8 524 810 32
[email protected]
ki.se/bionut/garoff
Löving R., Wu S-R., Sjöberg M., Lindqvist B.
and H. Garoff. (2012) Maturation cleavage
of the retrovirus spike precursor splays the
transmembrane subunits to prime it for receptor
triggering. Proc. Natl. Acad. Sci. USA.
109:7735-7740.
Löving R., Kronqvist M., Sjöberg M. and H.
Garoff. (2011) Cooperative cleavage of the Rpeptide in the Env trimer of the Moloney murine
leukemia virus facilitates its maturation for
fusion competence. J. Virol. 85:3262-3269.
Activation of HIV-1 and
murine leukemia virus
for cell entry
Nuclear receptors in health
and disease
Retroviruses like HIV-1 and murine leukemia
virus (MLV) enter into cells trough fusion of
the viral membrane with the cell membrane.
This process is mediated by the viral spike proteins. We like to know how the spike proteins
are activated for membrane fusion and how
neutralizing antibodies (Abs) are able to inhibit
spike activation. In our studies Ab-bound or
unliganded spikes of HIV-1 and MLV are triggered by receptor binding or other conditions
to convert into structural intermediates of the
activation pathway. The spikes are then solubilized with mild detergents and isolated for
structural analyses using biochemical methods
and cryo-electron microscopy.
Nuclear receptors (NRs) are ligand-activated
transcription factors that encompass receptors
for steroid hormones as well as receptors acting
as sensors of metabolic compounds such as
oxysterols and fatty acids. NRs can control intermediary metabolism as well as cellular proliferation and there is a growing appreciation
that NRs could be more widely used as targets
for treatment of various diseases. We focus our
research on the estrogen receptors (ERs) and
the liver X receptors (LXRs). Subtypes of these
receptors, α and β, are encoded by different
genes and ERβ and LXRβ were discovered in
our group.
Recently we showed how the newly made MLV
spike matures stepwise in the infected cell into
a form that is primed for receptor induced
activation. Using HIV-1 we have isolated and
characterized spikes in their native and activated intermediate form and elucidated how two
broadly neutralizing Abs inhibit the activation.
The results explain how the individual protomers of the trimeric spike coordinate their
activation. Furthermore, the study also suggests
novel ways to produce stabile native spikes to
be used as a HIV-1 vaccine.
Tissue specific NR knock-outs
Crucial for our research are mouse models with
specific deletions of the receptors and we have
Sjöberg M, Lindqvist B. and H. Garoff. (2011)
The activation of the alphavirus spike is suppressed by bound E3. J. Virol. 85:5644-5650.
Wu S.-R., Löving R., Lindqvist B., Hebert H.,
Koeck P. B. J., Sjöberg M. and H. Garoff. (2010)
Single-particle cryoelectron microscopy analysis
reveals the HIV-1 spike as a tripod structure.
Proc. Natl. Acad. Sci. USA 107:1884418849.
shown that the subtypes often have distinct and
sometimes even opposite roles. The role of ERs
is specifically addressed in relation to breast,
prostate and colon cancer and a concept of yin
and yang has emerged; ERβ having anti-proliferative pro-differentiative effects. An anti-proliferative effect of LXRβ in colon has also been
demonstrated. Our recent studies suggest that
diseases of the CNS like Parkinson´s disease
and ALS may involve a component of aberrant
LXRβ signaling. LXRβ is indicated to play a
protective role also in the prevention of bone
diseases. We have now generated floxed ERα,
ERβ, LXRα and LXRβ mice that will be used to
knock out the receptors in selected tissues by
using the Cre/LoxP system in order to further
advance our understanding of these receptors.
Jan-Åke Gustafsson
+46 8 524 811 46
+1 713 409 6743
[email protected]
ki.se/bionut/gustafsson
Suzuki H, Barros RP, Sugiyama N, Krishnan V,
Yaden BC, Kim HJ, Warner M, Gustafsson JA.
(2012) Gustafsson, Involvement of estrogen
receptor beta in maintenance of serotonergic
neurons of the dorsal raphe. Mol. Psychiatry,
Epub ahead of print.
Dai Y.-B., Tan X.-J., Wu W.-F., Warner M. and
Gustafsson J.-Å. (2012) MPTP hypersensitivity
in Liver X Receptor beta knockout mice and
neuroprotection of WT mice by Liver X Receptor
agonist. Proc. Natl. Acad. Sci. 107:1311213117.
Tan XJ, Dai YB, Wu WF, Kim HJ, Barros RP,
Richardson TI, Yaden BC, Warner M, McKinzie
DL, Krishnan V, Gustafsson JÅ. (2012) Reduction
of dendritic spines and elevation of GABAergic
signaling in the brains of mice treated with
an estrogen receptor beta ligand. Proc. Natl.
Acad. Sci. USA 109:1708-1712.
Nilsson S, Koehler KF, Gustafsson JÅ. (2011)
Development of subtype-selective oestrogen
receptor based therapeutics. Nat. Rev. Drug
Develop. 10:778-792.
Thomas C, Gustafsson JÅ. (2011) The different
roles of ER subtypes in cancer biology and therapy. Nature Reviews Cancer 11:597-608.
Group members
Maria Ekström
Kejun Li
Birgitta Lindqvist
Robin Löving
Kimmo Rantalainen
Mathilda Sjöberg
Michael Wallin
Shang-Rung Wu
14
Group members
Maturation and activation of the MLV spike. The spike is made as a precursor trimer, which matures by
two cleavages. First furin cleaves the receptor binding SU subunit from the transmembrane TM with fusion
activity and then, in newly made virus, the viral protease cleaves a peptide, the R-peptide, from the endodomain of TM. 3-D structures at 18 Å resolution are shown for the MLV spike in its precursor, mature and
activated intermediate forms in side and top views. The protomeric unit of the trimer forms upper, middle
and lower protrusions, where the upper represents the receptor binding domain (RBD) of SU, the middle
the C-terminal domain of SU and the lower the TM subunit. It is shown how the lower TM protrusions are
spread out by the maturation cleavage and how the spike activation opens a hole in the spike roof through
relocation of the RBDs. This supports a model where the TM subunits must be released in order to refold
into fusion active forms that can reach the target membrane through a hole in the spike roof.
Christina AnderssonThulin
Per Antonson
Amena Archer
Maria Bondesson
Chiara Gabbi
Lars-Arne Haldosén
Karin Edvardsson
Treska Hassan
Patricia Humire
José Inzunza
Tomas Jakobsson
Anna Klopot
Marion Korach-André
Karolina Lindberg
Agneta Mode
Yoko Omoto
Kirsten Remen
Knut Steffensen
Lise-Lotte Vedin
Margaret Warner
AnneMarie Witte
15
Hans Hebert
+46 8 524 810 93
[email protected]
ki.se/bionut/hebert
Gustafsson JK, Ermund A, Ambort D, Johansson ME, Nilsson HE, Thorell K, Hebert H,
Sjövall H, Hansson GC. (2012) Bicarbonate and
functional CFTR channel are required for proper
mucin secretion and link cystic fibrosis with its
mucus phenotype. J Exp Med. 209:1263-72.
Ambort D, Johansson ME, Gustafsson JK, Nilsson HE, Ermund A, Johansson BR, Koeck PJ,
Hebert H, Hansson GC. (2012) Calcium and
pH-dependent packing and release of the gelforming MUC2 mucin. Proc Natl Acad Sci U S
A. 109:5645-50.
Brismar TB, Grishenkov D, Gustafsson B, Härmark J, Barrefelt A, Kothapalli SV, Margheritelli
S, Oddo L, Caidahl K, Hebert H, Paradossi G.
(2012) Magnetite nanoparticles can be coupled
to microbubbles to support multimodal imaging.
Biomacromolecules. 13:1390-1399.
Cryo electron microscopy of
membrane proteins and
biomolecular assemblies
Structural studies of eggsperm interaction and human
hedgehog signaling proteins
Mucins are large glycoproteins that coat the
surface of cells in the respiratory, digestive,
and urogenital tracts. The first insights into the
packing and secretion of intestinal MUC2 in
molecular terms have now been obtained. Purified MUC2-N protein was analyzed by electron
microscopy and image processing, suggesting
how MUC2-N is packed in granulae of goblet
cells. Dysregulation of the normal >1000fold expansion upon release could explain the
extreme viscosity of the produced mucus seen
in cystic fibrosis.
Species-restricted recognition between egg and
sperm at fertilization is one of the most crucial
steps of development. However, despite decades
of investigation, the molecular mechanism
of this essential process remains unknown.
Our group uses mammalian cell expression to
overproduce in recombinant form the highly
posttranslationally modified molecules that are
involved in gamete interaction, for both biochemical and X-ray diffraction studies. During
the last few years, we determined crystallographic structures of ZP3, a major glycoprotein
component of the specialized extracellular coat
of the egg that first contacts sperm at conception. This gave insights into the evolution of
egg coat architecture from invertebrates to
human, and suggested that a glycan conserved
from birds to mammals plays an important role
A refined atomic model of microsomal glutathione transferase 1 in a lipid bilayer environment has been determined using electron
crystallography. It is shown that glutathione
binds in a different conformation as compared
to other proteins from the same superfamily.
Information unique to the methodological
approach shows interactions between lipids
and protein. Furthermore, we have determined
conformational changes occurring as a result of
second substrate binding giving further insight
into the catalytic mechanism. Key residues
determining species differences in inhibitor
binding of microsomal prostaglandin E synthase-1 have been identified.
Structural studies of a putative potassium
channel suggest a new arrangement the soluble
domains regulating the conductance of K+-ions
in these types of channels.
The properties of polymer microbubbles,
intended to be used for multimodal medical
imaging, have been studied by electron microscopy both with regard to ultrastructure and
distribution in different organs.
in sperm binding. Ongoing projects aim at characterizing complexes between gamete recognition proteins, with possible future application
to the understanding of human infertility and
the design of targeted non-hormonal contraceptives.
In parallel with our work on fertilization, we
have a long term collaboration on human
hedgehog signaling proteins with the group of
Prof. Rune Toftgård. Recently we determined
the structure of full-length tumor suppressor
SUFU, a key regulator of the pathway in mammals. This led to the identification of a large
regulatory region of the protein, whose interaction with the Gli family of transcription factors
is currently being addressed.
16
Sutton, K. A., Jungnickel, M. K., Jovine, L.
and Florman, H. M. (2012) Evolution of the
voltage sensor domain of the voltage-sensitive
phosphoinositide phosphatase VSP/TPTE suggests a role as a protein channel in eutherian
mammals. Mol. Biol. Evol. 29:2147-2155.
Jovine, L. (2011) X-ray of fertilization. Mol.
Reprod. Dev. 78:1.
Monné M, Jovine L. (2011) A structural view of
egg coat architecture and function in fertilization Biol Reprod. 85:661-669.
Swanson WJ, Aagaard JE, Vacquier VD, Monné
M, Sadat Al Hosseini H, Jovine L. (2011) The
molecular basis of sex: linking yeast to human
Mol Biol Evol. 28:1963-1966.
Group members
Marcel Bokhove
Amy Cherry
Elisa Dioguardi
Ling Han
Kaoru Nishimura
Hamed Sadat Al Hosseini
Takako Saito
Cheng, K., Ivanova, N., Scheres, S.H.W., Pavlov,
M.Y., Carazo, J.M., Hebert, H., Ehrenberg, M.
and Lindahl, M. (2010) tmRNA-SmpB complex
mimics native aminoacyl-tRNAs in the A site of
stalled ribosomes. J Struct Biol. 169:342-348.
Martin Lindahl
Harriet Nilsson
Pasi Purhonen
Rampradeep Samiappan
Lin Zhu
Han L, Monné M, Okumura H, Schwend T,
Cherry AL, Flot D, Matsuda T, Jovine L. (2010)
Insights into egg coat assembly and egg-sperm
interaction from the X-ray structure of fulllength ZP3. Cell 143:404-415.
Pawelzik, S., Narasimha, R.U., Spahiu, L., Jegerschöld, C., Stenberg, P., Hebert, H., Morgenstern, R. and Jakobsson, P-J. (2010) Identification
of key residues determining species differences in
inhibitor binding of microsomal prostaglandin e
synthase-1. J Biol Chem. 285:29254-61.
Group members
Kimberley Cheng
Johan Härmark
Caroline Jegerschöld
Philip Koeck
Qie Kuang
Ramki Kumar
Luca Jovine
+46 701 497 014
[email protected]
ki.se/bionut/jovine
The membrane-bound detoxification enzyme microsomal glutathione transferase 1. The electron diffraction pattern was recorded from a two-dimensional crystal of the protein. The inset shows the corresponding 3D map at 3.5 Å resolution as reconstructed from a large number of such patterns obtained from a
distribution of projection directions. The viewing direction is perpendicular to the plane of the membrane.
Each triangular structure corresponds to one trimer of the protein having twelve transmembrane alpha
helices.
Crystal of ZP3, the conserved vertebrate egg coat protein that first binds sperm at the beginning of
fertilization.
17
Maria Kasper
+46 8 524 811 67
[email protected]
ki.se/bionut/kasper
Kasper M, Jaks V, Hohl D and Toftgård R.
(2012) Basal Cell Carcinoma – molecular biology and potential new therapies. J Clin Invest.
122(2):455-63.
Sonkoly E, Lovén J, Xu N, Meisgen F, Wei T,
Brodin P, Jaks V, Kasper M, Shimokawa T,
Harada M, Heilborn J, Hedblad MA, Hippe A,
Grandér D, Homey B, Zaphiropoulos P, Arsenian-Henriksson M, Ståhle1 M, Pivarcsi A. (2012)
MicroRNA-203 Functions as a Tumor Suppressor
in Basal Cell Carcinoma. Oncogenesis.1:e3.
Kasper M, Jaks V, Are A, Bergström Å, Schwäger
A, Barker N and Toftgård R. (2011) Wounding
enhances epidermal tumorigenesis by recruiting
hair follicle keratinocytes. Proc Natl Acad Sci
USA. 108(10):4099-104.
Stem cell dynamics in skin
- from homeostasis to cancer
Molecular genetics and
biology of complex diseases
Skin is an excellent tool to study the onset of
cancer since the epidermis of the skin is one of
the best-studied stem cell systems and cancer
is believed to arise from deregulated stem cell
populations. Epidermal stem cells are located
in distinct niches of the hair follicle and the interfollicular epidermis and their respective progeny are restricted to defined areas. However,
injuries like acute wounds disturb the balance
of homeostasis and allow stem cell progeny to
repopulate new areas. Cancer also disturbs - or
needs a disturbed - homeostasis, thus it is not
surprising that wound healing and cancer are
closely related processes.
Our group’s research focuses on the discovery
of gene effects in complex human phenotypes,
functional annotation of genes and characterization of gene networks in selected diseases.
Three major projects involve the epigenetics
and genetics of asthma and allergies (EpiGene
project; Reinius & al. 2012, see selected publications), gene networks in dyslexia (Massinen
& al. 2011, Tammimies & al. 2012), and human
embryonal development from oocyte to implantation (unpublished). In addition, we have
been characterizing the population structure of
Sweden and Finland (Salmela & al. 2011).
By using a wide range of techniques we are
addressing three different, yet tightly linked key
questions:
1. What is the cellular diversity of stem cells in
epidermal homeostasis? 2. What roles do distinct stem cell niches and
wound repair play in tumorigenesis?
3. What is (are) the molecular fingerprint(s) of
newly transformed cancer-initiating cells?
In summary, our aim is to unravel stem cell
diversity and plasticity in adult tissue, and
to reveal how wound repair and stem cell
reprogramming influence the development of
non-melanoma skin cancer, the most common
cancer worldwide. We hope to find very basic
mechanisms governing cancer initiation with
potential for generalization to many types of
cancer.
Our group is interdisciplinary and includes
members with solid background in genetics,
biochemistry, molecular and cellular biology,
biostatistics, bioinformatics, and model systems
(mouse and zebrafish). We work in tight collaboration with clinical specialists and epidemiologists as well as leading experts on special
methodologies, such as single-cell transcriptomics and brain imaging, and are involved
in international consortia. We use modern
genomics tools such as high-throughput sequencing for discovering gene variants and for
gene expression profiling (RNAseq). We have
tight collaboration with University of Helsinki
where Prof. Kere visits part-time based on a
specific contract. This group structure provides
an excellent training environment for both
post- and predoctoral scientists.
Tammimies K, et al. (2012) The molecular
networks of the DYX1C1 gene show connection
to neuronal migration genes and cytoskeletal
proteins. Biol Psychiatry epub ahead of
print.
Reinius LE, et al. (2012) Differential DNA
methylation in purified human blood cells: implications for cell lineage and studies on disease
susceptibility. PLoS ONE. 7:e41361.
Salmela E, et al. (2011) Swedish population
substructure revealed by genome-wide single
nucleotide polymorphism data. PLoS ONE
6:e16747.
Massinen S, et al. (2011) Increased expression
of the dyslexia candidate gene DCDC2 affects
length and signaling of primary cilia in neurons.
PLoS ONE 6:e20580.
Snippert HJ, Haegebarth A, Kasper M, Jaks V,
van Es JH, Barker N, van de Wetering M, van
den Born M, Begthel H, Vries RG, Stange DE,
Toftgård R, Clevers H. (2010) Lgr6 marks stem
cells in the hair follicle that generate all cell lineages of the skin. Science 327(5971):1385-9.
Anedda F, et al. (2011) Multiple polymorphisms
affect expression and function of the Neuropeptide S Receptor (NPSR1). PLoS ONE 6:e29523.
Jaks V, Kasper M and Toftgård R. (2010) The
Hair Follicle – a Stem Cell Zoo. Exp Cell Res.
316(8):1422-8.
Clonal expansion of individual Lgr5+ hair follicle
stem cells marked by the expression of distinct
fluorescent proteins. The stem cells were marked
in the resting phase (telogen) and their progeny
captured during the active growing phase (anagen) of the hair cycle.
Group members
Gayathri Chandrasekar
Pauliina Damdidopoulou
Elisabet Einarsdottir
Ingegerd Fransson
Dario Greco
Hong Jiao
Tiina M. Järvinen
Shintaro Katayama
Kaarel Krjutškov
Elo Madissoon
Hans Matsson
Christina Orsmark-Pietras
Helena Persson
Illustration: Reinius & al. 2012.
Group members
Alexandra Are
Anja Füllgrabe
Simon Joost
18
Juha Kere
+46 8 524 810 57
[email protected]
ki.se/bionut/kere
Hanna Peterson
Myriam Peyrard
Lovisa E. Reinius
Gustaf Rosin
Tiina Skoog
Cilla Söderhäll
Kristiina Tammimies
Isabel Tapia Paez
Ettore Tiraboschi
Virpi Töhönen
Liselotte Vesterlund
Jingwen Wang
Differences in DNA methylation between different white blood cell types are large and have implications
for whole-blood methylation analyses. Methylation profiles (as assayed by the Illumina 450K methylation
arrays) from six donors cluster in principal component analysis by cell type rather than individual variation.
19
Marie Löf
+46 8 524 810 95
+46 734 426 417
[email protected]
ki.se/bionut/lof
Lagerros YT, Sandin S, Bexelius C, Litton JE, Löf
M. (2012) Estimating physical activity using
a cell phone questionnaire sent by means of
short message service (SMS): a randomized
population-based study. Eur J Epidemiol.
27(7):561-6.
Eriksson, Henriksson H, Löf M, Hannestad U,
Forsum E. (2012) Body composition development during early childhood and energy
expenditure in response to physical activity
in 1.5-year-old children. Am J Clin Nutr.
96:567–73.
Early-life factors important
for childhood obesity: observational and interventional
Analytical toxicology and
clinical applications
According to WHO, childhood obesity is one
of the most serious public health challenges
of the 21st century. The mechanisms underlying overweight and obesity in young children
are largely unknown, but factors early in life,
maybe already in utero may be important. In
her research Marie studies early-life factors
that may be important for the establishment of
high body fatness. She is especially interested in
interactions between physical activity and body
fatness during the first years of life. She also
develops and evaluates preventive strategies to
counteract the development of overweight and
obesity during early childhood. Her research
involves observational as well as intervention
studies.
Nano-structures
The research is directed towards human cells
and clinical applications. In the Stockholm Particle Group network (KI, KTH, SU) the focus is
on nano-structures towards drug delivery or as
general exposure of ultrafine particles.
Another area of Marie’s research concerns
development and evaluation of methodology
important for nutritional assessments. This
work includes methodology to assess intake
of foods and energy, physical activity and
body composition. Recently this interest has
primarily focused on the possibilities of using
telecommunication technologies, such as
mobile phones, to improve dietary and physical
activity assessments in different populations.
Part of this work involves the development and
validation of a mobile phone questionnaire to
assess physical activity levels appropriate for
large-scale studies (see publications 1 and 2).
Bexelius C, Sandin S, Trolle Lagerros Y, Litton
JE, Löf M. (2011) Estimation of physical activity
levels using cell phone questionnaires: a comparison with accelerometry for evaluation of
between-subject and within-subject variations. J
Med Internet Res. 13:e70.
Löf M. (2011) Physical activity pattern and
activity energy expenditure in healthy pregnant
and non-pregnant Swedish women. Eur J Clin
Nutr. 65:1295-301.
A unique artificial lung is constructed were
nano-structures can be generated and transported in a way that a mono-layer of human
lung cells will be exposed. The mechanisms,
interaction with DNA (lesions) and oxidation
(ageing) of DNA are then investigated in vitro
under relevant human conditions.
Antioxidants
Other components that can damage DNA are
antioxidants, for instance vitamins, that easily
can shift to act as oxidants. Vitamins A and
C can at physiological levels oxidize DNA.
This effect can be increased if “minerals” are
present. Minerals are often metals that can
catalyze oxidative processes. Interestingly,
the scientific literature report negative effects
(increase of cancer and mortality) of vitamin
supplementations in western populations. The
best way to take vitamins and antioxidants is
to eat fruit and vegetables, then it is impossible
to over dose. Further, the artificial antioxidants like vitamin E is one component. In
fruit and vegetables there is a mixture of eight
varieties of vitamin E. That difference make a
difference.
Clinical studies
Several diseases have oxidative processes as a
key issue and therefore the in vitro data can
be applied to animal studies and/or clinical
situations. Clinical studies are performed
to investigate interactions, optimization of
clinical treatments and reduction of oxidative
symptoms. Drug developments are ongoing
regarding transplantation, prostate disease and
inflammatory diseases. Further, clinical studies
are investigated by the Comet Assay (50-100
cells are enough) and are applied to kidney
disease, environmetal exposure and other relevant clinical situations.
Eriksson B, Löf M, Forsum E. (2010) Body composition in full-term healthy infants measured
with air displacement plethysmography at 1 and
12 weeks of age. Acta Paediatr. 99: 563-8.
Cronholm P, Midander K, Karlsson H, Elihn K,
Odnewall Wallinder I, Möller L (2011) Effect of
sonication and serum proteins on copper release
from copper nanoparticles and the toxicity
towards lung epithelial cells. Nanotoxicology,
5, 269-281.
Ersson C, Odar-Cederlöf I, Fehrman-Ekholm I,
Möller L. (2012) The effects of hemodialysis treatment on the level of DNA strand breaks and
oxidative DNA lesions measured by the comet
assay. Hemodialysis International, Epub
ahead of print.
Shi J, Hedberg Y, Lundin M, Odnevall Wallinder
I, Karlsson HL, Möller L. (2012) Hemolytic
properties of synthetic nano- and porous silica
particles: The effect of surface properties and the
protection by the plasma corona. Acta Biomaterialia 8:3478–3490.
Bergström T, Ersson C, Bergman J and Möller
L. (2012) Vitamins at physiological levels cause
oxidation to the DNA nucleoside deoxyguanosine and to DNA—alone or in synergism with
metals. Mutagenesis 27(4):511–517.
Elihn K, Cronholm P, Karlsson HL, Midander K,
Odnevall Wallinder I and Möller L. (2012) Cellular Dose of Partly Soluble Cu Particle Aerosols
at the Air–Liquid Interface Using an In Vitro
Lung Cell Exposure System. Journal of Aerosol
Medicine and Pulmunary Drug Delivery,
epub ahead of print.
Group members
Eva Flinke Carlsson
Hanna Henriksson
Pontus Henriksson
Caroline Törnqvist
Measurement of body fatness using the pediatric option for BodPod.
20
Lennart Möller
+46 8 524 810 75
[email protected]
ki.se/bionut/moller
A nano-particle cluster (red) that has moved all the way into the nucleus (blue) of a cell where it hits DNA
(oxidation, aging of DNA, or DNA strand breaks). There are only a few papers in the literature that have
been able to visualize nano-structures reaching the cell nucleus.
Group members
Pontus Cronholm
Karine Ehlin
Clara Ersson
Johanna Kain
Hanna Karlsson
Siiri Lavatola
Staffan Larsson
Ylva Rodhe
Jingwen Shi
Therese Woodhill
Hanna Zandén
Rickard Åsgård
21
Simulating the behavior of
proteins and nucleic acids
Lennart Nilsson
+46 8 524 810 99
[email protected]
ki.se/bionut/nilsson
Allnér O, Nilsson L, Villa A. (2012) Magnesium
Ion–Water Coordination and Exchange in Biomolecular Simulations. Journal of Chemical
Theory and Computation.
Foloppe N, Vlamis-Gardikas A, Nilsson L.
(2012) The -Cys-X1-X2-Cys-Motif of Reduced
Glutaredoxins Adopts a Consensus Structure
That Explains the Low pKa of Its Catalytic
Cysteine. Biochemistry 51(41):8189-8207.
Ito M, Johansson J, Strömberg R, Nilsson L.
(2011) Unfolding of the Amyloid-Peptide Central
Helix: Mechanistic Insights from Molecular Dynamics Simulations. PLoS ONE 6(3):e17587.
Molecular dynamics simulations of the tRNA
anticodon and mRNA codon, inside the
ribosome 30S subunit, show that the common
tRNA modifications cmo5U34 and m6A37 in
tRNAVal, which allow all four nucleotides to
be successfully read at the wobble position in
a codon, may work through two mechanisms:
The further reach of the cmo5U34 modification allows an alternative conformation to be
formed for the noncognate base pairs, and
increased contacts between tRNA, mRNA, and
the ribosome. One intricate issue that requires
much attention is the corretct handling, and
placement of Mg2+ ions.
Polymerization of the amyloid β-peptide (Ab)
requires the helical structure of Ab to unfold.
The effects of two ligands, which were designed
to bind to and stabilize the helix, on unfolding
of the Ab central helix were investigated by MD
simulations.We quantitatively showed that both
ligands increase the stability of the Ab helix,
which correlates well with previous experiments for these ligands.
The dissociation mechanism of thioredoxin
(Trx) mixed disulfide complexes is unknown
We studied mixed disulfide dissociation in
arsenate reductase using theoretical reactivity
analysis, molecular dynamics simulations, and
biochemical complex formation experiments
with Cys-mutants. This lead to a universal
thiol/disulfide exchange reaction mechanism
that results in reduced substrate and oxidized
Trx.
Denning EJ, Priyakumar UD, Nilsson L, Mackerell AD. (2011) Impact of 2'-hydroxyl sampling
on the conformational properties of RNA:
Update of the CHARMM all-atom additive
force field for RNA. Journal of Computational
Chemistry 32(9):1929-1943.
Effects of glucocorticoids and
estrogens on cells and functions of the immune system
Hormonal effects on the immune system are
more or less well known. An example of the
former is the anti-inflammatory activity of
glucocorticoids (GCs), although still not all
molecular details have been elucidated. A
less known topic is the role and regulation of
the de novo synthesis of GCs locally in the
thymus, were it seems to have a paracrine role
regulating thymocyte homeostasis and T cell
development. Less established is also the effect
of estrogens on cells of the immune system and
particularly on tumors originating from lymphoid cells. The research projects of the group
aim to elucidate molecular mechanisms that
are involved in regulating physiological GC and
estrogen effects on the immune system.
Two main areas are studied:
1. Role and regulation of GCs locally produced in the thymus for T cell development
and function.
We and others have demonstrated a de novo
synthesis of GCs in several extra-adrenal tissues including the thymus, intestinal epithelium and the skin were the local synthesis seems
to play an important role for cell development
or local defense (1). We are particularly inte-
Allnér O, Nilsson L. (2011) Nucleotide modifications and tRNA anticodon–mRNA codon interactions on the ribosome. RNA 17:2177-2188.
rested in the role and regulation of GCs locally
produced in the thymus for T cell development and function (2,3). Furthermore, we are
interested in signaling pathways and cross-talk
mechanisms involved in the anti-inflammatory
action of GCs. A main mechanism for the antiinflammatory action of GCs is the cross-talk
between GC signaling and the NF-κB signaling
pathway. We perform studies to further understand the mechanisms in this cross-talk (4).
2. Understanding the antiproliferative
and tumor inhibiting effects of estrogen
receptor β (ERβ) agonists on malignancies
of lymphoid origin.
Lymphomas are generally not considered as
endocrine related diseases. However, epidemiological data clearly demonstrate a gender
difference in incidence and prognosis and a
possible impact of estrogens. We have demonstrated that several murine or human lymphomas do express ERβ and are highly sensitive to
ERβ agonists that cause an inhibition of tumor
growth in vivo (see figure and ref. 5). Using
various techniques (xenograph and cell experiments, gene expression studies) we are studying
the molecular mechanism responsible for this
tumor inhibiting effect by ERβ agonists.
Group members
Olof Allnér
Mauricio Esguerra
Mikael Gillner
Katarina Hart
Mika Ito
Alok Juneja
Andrey Karshikoff
Grzegorz Raszewski
Alessandra Villa
You Xu
Chen, Y., Qiao, S, Tuckerman, J., Okret, S. and
Jondal M. (2012) Thymus-derived glucocorticoids mediate androgen effects on thymocyte
homeostasis FASEB J. 24:5043-5051.
Moors, M., Bose, R., Johansson-Haque, K.,
Tofiqhi, R., Okret, S. and Ceccatelli, S. (2012)
Dickkopf 1 mediates glucocorticoid-induced
changes in human neural progenitor cells proliferation and differentiation. Toxic. Sci. 125,
488-495.
Yakimchuk K, Nandakumar KS, Chen L,
Holmdahl R, Okret S and Jondal M. (2012)
Keratinocyte growth factor (KGF) delays the
onset of collagen-induced arthritis. Autoimmunity, 45, 510-515.
Yakimchuk, K., Iravani, M., Sharif Hasni, M.,
Rhönnstad, P., Nilsson, S., Jondal, M. and Okret,
S. (2011) Effect of ligand-activated estrogen
receptor on lymphoma growth in vitro and in
vivo. Leukemia 25:1103-1110.
Group members
Jiyu Guan
Anna Ingemarsdotter
Krishan Johansson Haque
Elanchelian Palanichamy
Mohammad Sharif Hasni
Konstantin Yakimchuk
Consensus structure of the -Cys-X1-X2-Cys- active site motif in glutaredoxins.
22
Sam Okret
+46 8 524 810 69
[email protected]
ki.se/bionut/okret
Immunocompromised mice were injected with human lymphoma cells and treated with subcutaneous injections of the
ERβ agonist DPN.
23
Joseph Rafter
+46 8 524 83 545
+46 762 133 690
[email protected]
ki.se/bionut/rafter
Al-Asmakh M, Anuar F, Zadjali F, Rafter J, Pettersson S. (2012) Gut microbial communities
modulating brain development and function.
Gut Microbes 3: 366-73.
L. Renee Ruhaak, J. Felth, PC. Karlsson, J. Rafter,
R. Verpoorte, L. Bohlin. (2011) Evaluation of
the cyclooxygenase inhibiting effects of six major
cannabinoids isolated from Cannabis sativa.
Biol. Pharm. Bull. 34: 774-778.
L. Aronsson, Y. Huang, P. Parini, M. Korach-Andre, J-Å. Gustafsson, S. Pettersson, V. Arulampalam, J. (2010) Rafter, Decreased Fat Storage
by Lactobacillus Paracasei is Associated with
Increased Levels of Angiopoietin-Like 4 Protein
(ANGPTL4). PLoS ONE 5:e13087.
Host – microbe interactions
Childhood factors and
cardiovascular health
The human gut is colonized by billions of commensal microbes, which constitute a complex
and diverse community collectively known as
the gut microbiota. These microbes communicate with each other and the host (both locally
and systemically) through mechanisms not
fully understood. The microbiota exert positive
physiological and nutritional effects, and alterations in its composition are associated with
human conditions such as inflammatory bowel
disease, colon cancer and metabolic diseases.
Recently, it is becoming obvious that the microbiota are also involved in the maintenance of a
‘good health’.
The goal of the unit for Preventive Nutrition is
to contribute to the design of more successful
programs for prevention of cardiovascular
disease.
One of the interests of our work is to develop
biomarkers that can assess this latter effect.
We are also interested in identifying mole-
cular targets in host tissues, relevant to the
above conditions, which are regulated by the
microbiota.
Examples of such targets to date include nuclear receptors involved in inflammation and
metabolism and fasting-induced adipose factor
(FIAF), a lipoprotein lipase inhibitor, important
in fat storage regulation.
Therapeutic strategies must then be considered,
where modifications in the gut microbiota may
be introduced via pharmacological or dietary
changes, in order to restore “normal” intestinal
flora and human wellbeing. Thus, a major focus
of our work is attempting to modify identified/
relevant gut-regulated targets through modifying the diet with e.g. probiotic bacteria.
The objectives are:
• To deliver basic data on key early childhood
lifestyle and circumstantial factors, the
importance of physical activity and fitness
and gender differences.
• To analyze whether lifestyle factors at
childhood and adolescence predict later
cardiovascular risk.
• To study associations of changes in lifestyle
factors with changes in later cardiovascular disease.
• To determine whether the associations
between genetic variations and cardiovascular disease phenotypes are modified
by changes in lifestyle, i.e. gene-lifestyle
interactions.
Rabot S, Rafter J, Rijkers GT, Watzl B, Antoine
JM. (2010) Guidance for substantiating the evidence for beneficial effects of probiotics: impact
of probiotics on digestive system metabolism. J
Nutr. 140: 677S-89S.
During 2010 and 2012 we first focused on the
cross-sectional associations between lifestyle
factors and cardiovascular disease factors in
young people and then on longitudinal associations between lifestyle in childhood and
adolescence and future cardiovascular disease
risk. Life-style gene interactions and intergenerational epigenetically indicated inheritances
were also reported.
We used our own large scale cross-sectional,
longitudinal and pedigree epidemiological data.
Early fitness is associated with low adolescent
overweight and change in fitness still more so.
Insulin sensitivity at childhood predicts total
and central adiposity gain in adolescence. An
active lifestyle attenuates the effect of low birth
weight on adolescent insulin resistance, leptin
levels, obesity and interacts with the obesity
related FTO gene. Availability of food in sensitive childhood periods influences descendants´
cardiovascular health. The findings should
foster prevention programs that start early in
the atherosclerosis process.
• To study intergenerational responses to
early life nutrition indicative of nonsequential inheritance.
Rijkers GT, Bengmark S, Enck P, Haller D, Herz
U, Kalliomaki M, Kudo S, Lenoir-Wijnkoop I,
Mercenier A, Myllyluoma E, Rabot S, Rafter
J, Szajewska H, Watzl B, Wells J, Wolvers D,
Antoine JM. (2010) Guidance for substantiating
the evidence for beneficial effects of probiotics:
current status and recommendations for future
research. J Nutr. 140: 671S-6S.
Ortega FB,Ruiz JR, Hurtig-Wennlöf A, Meirhaeghe A, González-Gross M, Moreno
L, Molnar D, Kafatos A, Gottrand F, Widhalm
K, Labayen I, Sjöström M (2011) Physical
activity attenuates the effect of low birth weight
on insulin resistance in adolescents Findings
from two observational studies. Diabetes 60:
2295-2299.
Labayen I, Ruiz JR, Ortega FB, Loit HM, Harro
J, Villa I, Veidebaum T, Sjostrom M (2012)
Exclusive breastfeeding duration and cardiorespiratory fitness in children and adolescents. Am
J Clin Nutr. 95: 498-505.
Ortega FB, Silventoinen K, Tynelius P, Rasmussen F. (2012) Muscular strength in male adolescents and premature deathCohort study of one
million participants. BMJ. 04.345:e7279.
Nilsson TK, Yngve A, Böttiger AK, HurtigWennlöf A, Sjöström M. (2011) High folate
intake is related to better academic achievement
in Swedish adolescents. Pediatrics;128: 358365.
Group members
Lars Olov Bygren
Charlotte Goodrose-Flores
Lena Hallström
Gunnar Kaati
Lydia Kwak
Idia Labayen
Pekka Oja
Fransisco Ortega
Nico Rizzo
Jonatan Ruiz Ruiz
Petter Tinghög
Group members
Rossana D'Arienzo
Gut microbiota influence host physiology through local and systemic effects.
24
Michael Sjöström
+46 8 524 810 43
[email protected]
ki.se/bionut/sjostrom
An illustration of the independent data in the studies of transgenerational responses to availability of food,
that have indicated that epigenetic intergenerational inheritance might influence cardiovascular health.
25
Dan Segerbäck
+46 8 585 837 79
[email protected]
ki.se/bionut/segerback
Pedersen M, et al. (2012) Head Circumference, and Prenatal Exposure to Acrylamide from
Maternal Diet: The European Prospective
Mother-Child Study (NewGeneris). Environ
Health Perspect. 120:1739-45.
Liljendahl TS, Kotova N, Segerbäck D. (2012)
Quantification of ultraviolet radiationinduced DNA damage in the urine of Swedish
adults and children following exposure to
sunlight. Biomarkers. 17:634-41.
Singh R, Gromadzinska J, Mistry Y, Cordell
R, Juren T, Segerbäck D, Farmer PB. (2012)
Detection of acetaldehyde derived N(2)ethyl-2'-deoxyguanosine in human leukocyte
DNA following alcohol consumption. Mutat
Res. 737:8-11.
Kotova N, Jurén T, Myöhänen K, Cornelius
M, Abramsson-Zetterberg L, Backman J,
Menzel U, Rydberg P, Kronberg L, Vähäkangas K, Segerbäck D. (2011) ³²P-HPLC
analysis of N1-(2-carboxy-2-hydroxyethyl)
deoxyadenosine: a DNA adduct of the
acrylamide-derived epoxide glycidamide.
Toxicol Lett. 207:18-24.
Monitoring human exposure
to ultraviolet radiation
Nucleic acids and peptides in
biotechnology and therapy
The work on UV has been focused on the
analysis of thymidine dimer (T=T) in urine
within the EU project ICEPURE. Quantification of T=T in urine samples collected before
and after various outdoor activities showed that
high levels were formed when spending one
week at the island Tenerife, but not when skiing
during one week in the Alps (limited skin
exposure during such activities). In another
setting people were experimentally exposed to
full body UV radiation and skin biopsies and
urine samples collected at different time points
after exposure. The analyses of T=T showed
that there was a correlation between T=T in the
urine and in the skin and that morning urine
samples well reflected T=T levels in 24 h urine
samples. In other UV-related projects we have
shown that there was no difference in urinary
Oligonucleotide Based Artificial Nucleases and PNAzymes. Artificial enzymes
are developed, including PNAzymes that are
world leading artificial ribonucleases and the
first truly artificial RNA restriction enzymes.
These tailor-made RNases, are usable tools for
molecular biology and is currently developed
further to obtain a cleavage rate that may allow
use in therapy.
T=T levels between children and adults after
spending 1-2 days on a beach in summer time
Stockholm and that the amount of T=T was
correlated to the UV dose. We also demonstrated that very high levels of T=T can be detected
in lifeguards working on a beach in southern
Sweden and that some kind of steady-state level
is reached after longer exposures.
For the work on chemical exposures within the
EU projects ECNIS and NewGeneris we have
participated in the analysis of DNA adducts of
acetaldehyde in people drinking alcohol and
in a large human study in which it was showed
that high levels of hemoglobin adducts of
acrylamide in fetal blood was associated with a
reduced birth weight.
Stabilised, Cell Penetrating and Target
Seeking Oligonucleotides for Enhanced Therapy. A novel approach based on a synthetic
2,2,7-trimethylguanosine Cap (m3G-Cap) NLS
and oligonucleotides (ONs) with an incorporated m3G-Cap gave enhanced splice correction.
Modified m3G-CAP’s that are more resistant to
degradation is now pursued. Another development is cell penetrating oligonucleotides (CPO)
that are taken up spontaneously and also are
highly resistant towards enzymatic degradation, which suggest high potential for use in
ON therapy. Further developments includes designed nano-constructs that contain elements
of recognition (ON), tissue targeting (e.g.
homing peptides), cell permeation elements
(CPO etc) and nuclear delivery signals.
Helix Stabilisers that Inhibit Aβ-Peptide
Aggregation – A New Concept for Potential
Treatment/Prevention of Alzheimers Disease. We have developed ligands that stabilise
the Aβ peptide in the native helical conformation. These prevent Aβ induced reduction in
hippocampal γ-oscillations (that is connected
to cognition and learning and reduced in
patients with AD) and oral administration of ligands increase longevity and decrease locomotor dysfunction in a Drosophila model of AD.
As the approach holds promise for treatment of
AD we are developing improved ligands.
Treatment of infections through substances
that induce our own defense against microbes. Another goal is treatment of infections, in
particular by multiresistant bacteria, through
induction of body-own antimicrobial peptides.
Developed inducers give increased levels of
antimicrobial peptides both in the intestine and
respiratory tract. Treated animals get complete
recovery from shigellosis and a clinical trial for
treatment of TB has been initiated.
Roger Strömberg
+46 8 585 810 24
[email protected]
ki.se/bionut/stromberg
Honcharenko M., Romanowska J., Alvira M.,
Jezowska M., Kjellgren M., C. I. Edvard Smith
C. I. E. and Strömberg R. (2012) Capping of
Oligonucleotides with “Clickable” m3G-CAPs.
RSC Advances 2:12949-12962.
Murtola M, Wenska, M., Strömberg R. (2010)
PNAzymes that are artificial RNA restriction
enzymes. J. Am. Chem Soc. 132:8984–8990.
Wenska M, Steunenberg, P, Stenberg Å, Murtola, M and Strömberg R. (2011) An Activated
Triple Bond Linker Enables “Click” Attachment of
Peptides to Oligonucleotides. Nucl. Acids Res.
39:9047-9059.
Sarker, P, Ahmed, S, Tias, S, Rekha, R.S, Strömberg, R, Andersson, J Bergman, P, Gudmundsson, G.H, Agerberth, B & Raqib R. (2011)
Shigella mediated downregulation of cathelicidin in lung and colon epithelia is counteracted
by Phenylbutyrate: implication for a potential
therapeutic strategy. PLoS One, 6:e20637.
Milton S, Ander C, Yeheskiely E and Strömberg
R. (2012) Stability of a 2’-O-(carbamoylmethyl)
adenosine containing dinucleotide. Eur. J. Org.
Chem, 539-543.
Group members
Alice Ghidini
Dmytro Honcharenko
Malgorza Honcharenko
Martina Jezowska
Jyotirmoy Maity
Stefan Milton
Merita Murtola
Håkan Ottosson
Jessica Sandbrink
von Stedingk H, Vikström AC, Rydberg P, Pedersen M, Nielsen JK, Segerbäck D, Knudsen
LE, Törnqvist M. (2011) Analysis of hemoglobin adducts from acrylamide, glycidamide,
and ethylene oxide in paired mother/cord
blood samples from Denmark. Chem Res
Toxicol. 24:1957-65.
Group members
Tina Jurén
Annette Landström
Bobby Li
Tove Sandberg
Confocal microscopy of U2OS-cells treated with fluorescein-labeled (green color), non-modified ONs (left
panel) or with CPO-modified ONs (right panel).
26
27
Cell biology of cancer
Staffan Strömblad
+46 8 524 811 22
[email protected]
ki.se/bionut/stromblad
Smith, S., Enge, M., Bao., W., Thullberg, M.,
Costa, T.D.F, Gashi, B., Selivanova, G., and
Strömblad, S. (2012) PKCa regulates localization and melanoma cell survival downstream
of integrin alphaV in 3D collagen. J Biol Chem
287:29336-47.
Li, Z, Lock, J., Olofsson, H., Kowalewski JM, Teller, S, Liu, Y., Zhang, H., & Strömblad, S. (2010)
Integrin-mediated cell attachment induces a
PAK4-dependent feedback loop regulating cell
adhesion through modified integrin αvβ5 clustering and turn-over. Mol Biol Cell 21:317-29.
We aim to improve the fundamental understanding on how cancer develops and progresses. Our focus is cancer cell migration, a
process critical to cancer cell dissemination by
metastasis, the main lethality factor of cancer.
To better understand cancer cell migration,
we are using a systems microscopy approach,
where live cell microscopy of migrating cancer
cells is combined with mathematical analyses
and modeling. With the help of transgenic
mice, we are also investigating how p21-activated kinase 4 affects cancer development and
From the basic biology of
cilia to ciliopathy disease
states in humans
progression, and we are also examining how
the microenvironment's extracellular matrix
influences the same processes.
We perform a large number of national and
international collaborations and actively participate in different networks, including the European Union-FP7-Systems Microscopy Network of Excellence and Karolinska Institutet’s
Breast Cancer Theme Center (BRECT). Staffan
Strömblad is the Coordinator and Vice director,
respectively, for these two networks.
Plantard L., Arjonen A., Lock JG., Nurani G.,
Ivaska J., & Strömblad, S. (2010) PtdIns(3,4,5)P3
is a regulator of Myosin-X localization and filopodia formation. J Cell Sci. 123:3525-3534.
Li Z, Zhang H, Lundin L, Thullberg M, Liu Y,
Wang Y, Claesson-Welsh L, & Strömblad S.
(2010) p21-activated kinase 4 phosphorylation
of integrin {beta}5 Ser 759 and Ser 762 regulates
cell migration. J Biol Chem. 285:2369923710.
Group members
Zhangewen An
Ulrich Berge
Marianne van Dijk
Tania Fernandes Costa
Xiaowei Gong
Sara Göransson
Pablo Hernadez Varas
Gabriela Imreh
Mehrdad Jafari Mamaghani
Ammad Khan
28
Alexa Kiss
Jacob Kowalewski
Zhilun Li
John Lock
Helene Olofsson
Andrew Paterson
Hamdah Shafqat
Stephen Smith
Miao Zhao
Ting Zhuang
We have carried out searches for X-box
promoter motifs in several animal genomes
(C. elegans, Drosophila, mouse and humans)
and have successfully identified direct RFX
TF target genes, many of which we confirmed
to be involved in ciliogenesis by using various
assays in transgenic C. elegans worms and in
transfected mammalian cell lines. Accordingly
we were able to assign some of these ciliary
genes – upon malfunction – to being at the
root of a human disease class termed ciliopathies. We are working on cell biological aspects
of human brain-related, suspected ciliopathies.
We are also trying to tie together the different
biological functions (in ciliogenesis) of direct
RFX TF target genes by cross-comparing a
large number of candidate X-box regulated
genes in a variety of different genomes. With
these approaches we will be able to track the
RFX TF target gene module from basic biological function to disease states in humans.
Burghoorn J, Piasecki BP, Crona F, Phirke P,
Jeppsson KE, Swoboda P. (2012) The in vivo dissection of direct RFX-target gene promoters in C.
elegans reveals a novel cis-regulatory element,
the C-box. Dev Biol. 368(2):415-26.
O'Hagan R, Piasecki BP, Silva M, Phirke P,
Nguyen KC, Hall DH, Swoboda P, Barr MM.
(2011) The tubulin deglutamylase CCPP-1 regulates the function and stability of sensory cilia in
C. elegans. Curr Biol. 21(20):1685-94.
Massinen S, Hokkanen ME, Matsson H, Tammimies K, Tapia-Páez I, Dahlström-Heuser V,
Kuja-Panula J, Burghoorn J, Jeppsson KE, Swoboda P, Peyrard-Janvid M, Toftgård R, Castrén
E, Kere J. (2011) Increased expression of the
dyslexia candidate gene DCDC2 affects length
and signaling of primary cilia in neurons.
PLoS One. 6(6):e20580.
Ezcurra M, Tanizawa Y, Swoboda P, Schafer
WR. (2011) Food sensitizes C. elegans avoidance
behaviours through acute dopamine signalling.
EMBO J. 30(6):1110-22.
Images: Pablo Hernández- Varas.
Siu, M.K.Y., Chan, H-Y., Wong, E.S.Y., Kong,
D.S.H., Woo, N.W.S.,Tam, K.F., Chan, Q.K.Y.,
Ngan, H.Y.S., Zhang, H., Tsao, G.S.W., Strömblad, S., Cheung, A.N.Y. (2010) p21-activated
kinase 4 regulates c-Src, ERK1/2 and MMP2
and contributes to ovarian cancer progression and prognosis. Proc Natl Acad Sci USA
107:18622-18627.
Evolutionarily RFX transcription factors (TFs)
are present only in the unikonts: animals, fungi,
choanozoa and amoebozoa. RFX TFs have a
unique DNA binding domain with which they
bind to the X-box promoter motif (RFX = Regulatory Factor binding to the X-box). Thereby
they directly regulate their target genes. In
fungi RFX TFs regulate genes involved in cell
cycle control, while in animals RFX TFs regulate genes involved in the immune response
and in cilia formation and development.
Peter Swoboda
+46 8 585 837 34
[email protected]
ki.se/bionut/swoboda
Quantification of tension in cell-matrix adhesion complexes in living cancer cells. By use of a Biosensor
FRET probe, we quantify the tension applied to Vinculin in cell-matrix adhesion complexes (arrows). Color
coding shows the FRET ratio efficiency indicating high (blue) to low (red) tension. The images show the
leading edge of a migrating H1299 human non-small lung cancer cell at two different time points, 15 min
apart, where the tension in the adhesion complexes has changed over time together with morphological
alterations of the cell-matrix adhesion complexes. By use of quantitative image-derived data, multivariate
statistics and mathematical modeling, in this project we are elucidating the causal relationships between
intra-adhesion tension and adhesion complex dynamics, and how this in turn may affect cancer cell migration. The images were produced by a Nikon A1R confocal microscope using a 60X oil objective (N/A =
1.42), followed by image processing including intensity thresholding. Size bar (red) = 5 micrometers.
Piasecki BP, Burghoorn J, Swoboda P. (2010)
Regulatory Factor X (RFX)-mediated transcriptional rewiring of ciliary genes in animals. Proc
Natl Acad Sci U S A. 107(29):12969-74.
The head of the worm C. elegans is shown. Two bilaterally symmetrical “salt-tasting” sensory neurons are
marked with GFP. Through cell-specific genetic rescue experiments the neuron at the top has regained a
fully functional sensory cilium (arrowhead) and thus is able to “taste” salt (cf. calcium imaging trace at the
left). The neuron at the bottom remains mutant for cilium development and thus is not able to “taste” salt
(cf. calcium imaging trace at the left).
Group members
Anastasia Emmanouilidou
Karin Fürtenbach
Juan Carlos FierroGonzalez
Ida Klang
Gilbert Lauter
Junho Lee
Prasad Phirke
29
Systems biology group
Jussi Taipale
+46 8 585 868 95
[email protected]
ki.se/bionut/taipale
Wei GH, Badis G, Berger MF, Kivioja T, Palin
K, Enge M, Bonke M, Jolma A, Varjosalo M,
Gehrke AR, Yan J, Talukder S, Turunen M, Taipale M, Stunnenberg HG, Ukkonen E, Hughes
TR, Bulyk ML, Taipale J. (2010) Genome-wide
analysis of ETS-family DNA-binding in vitro and
in vivo. EMBO J. 29(13):2147-60.
Sur, I., Hallikas, O., Vähärautio, A., Yan, J.,
Turunen, M., Enge, M., Taipale, M., Karhu, A.,
Aaltonen, L. A., and Taipale, J. Mice. (2012)
Lacking a Myc Enhancer Element that Includes
Human SNP rs6983267 Are Resistant to Intestinal Tumors. Science, 338:1360-3.
Kivioja, T., Vähärautio, A., Karlsson, K., Bonke,
M., Enge, M., Linnarsson, S., and Taipale, J.
(2012) Counting absolute number of molecules
using unique molecular identifiers. Nature
Methods, Advanced Online Publication
9:72-4.
Group members
Sandra Augsten
Kashyap Dave
Martin Enge
Lijuan Hu
Emma Inns
Arttu Jolma
Åsa Kolterud
Jianping Liu
Reading the genome
We are interested in understanding how DNA
sequence determines where and when genes
are expressed. For this purpose, we have carried out analysis of in vitro binding specifies
of transcription factors (TFs) and now have a
collection of binding specificity models for the
majority of all human TFs. We will proceed to
use this information to identify gene regulatory elements that control cell growth during
normal development and cancer.
Counting molecules
In addition, to make analysis of gene expression more accurate, we have developed tools for
analysis of RNA levels in cells. We developed
together with Sten Linnarson lab a universal
method that can be applied to counting the
absolute number of molecules in a sample.
Application to cancer
We have identified earlier a gene regulatory
element that is located upstream of the Myc
oncogene. This element contains a SNP that
accounts for more human cancer-related
morbidity than any other genetic variant or
mutation. To characterize this potential regulatory element, we generated mice deficient in it.
The mutant mice displayed no overt phenotype
but were resistant to intestinal tumorigenesis
induced by the APCmin mutation highlighting
the fact that although a disease-associated
polymorphism typically has a relatively modest
effect, the element that it affects can be critically important for the underlying pathological
process.
Inappropriate reactivation of developmental
signalling pathways such as the Hedgehog (Hh)
pathway is a common event during cancer
development. Mutational inactivation or activation of core components of the Hh-pathway
underlies cell autonomous activation in basal
cell carcinoma of the skin (BCC) and in medulloblastoma. In other tumour types such as
pancreatic cancer and breast cancer additional
activation mechanisms are present.
A major focus of our research is to understand
the details of Hh signalling at the genetic,
molecular and structural level with emphasis on the key intracellular SUFU and GLI
components. Secondly, to understand how
aberrant activation of this pathway can drive
cancer development in skin, mammary gland
and pancreas combining studies of genetically
modified preclinical models and of human tissues. Thirdly, to devise new methods aimed at
pharmacological inhibition of the Hh signalling
pathway at the level of the GLI transcriptional
effectors building on our detailed biological
and molecular studies of the pathway.
To understand cancer biology and how to
best eradicate tumour cells we must know the
biology of normal tissues including the nature
of tissue stem and progenitor cells, their interconversions and their ability to serve as cancer
cell of origin. With this aim we investigate the
presence and functional properties of tissue
stem cells marked by expression of Lgr5 and
Lgr6 in human and murine skin and mammary
gland.
Rune Toftgård
+46 8 524 810 53
[email protected]
ki.se/bionut/toftgard
Kasper M, Jaks V, Hohl D, Toftgård R. (2012)
Basal cell carcinoma - molecular biology
and potential new therapies. J Clin Invest.
122(2):455-63.
Kasper M, Jaks V, Are A, Bergström Å, Schwäger
A, Svärd J, Teglund S, Barker N, Toftgård R.
(2011) Wounding enhances epidermal tumorigenesis by recruiting hair follicle keratinocytes.
Proc Natl Acad Sci U S A. 108(10):4099104.
Snippert HJ, Haegebarth A, Kasper M, Jaks V,
van Es JH, Barker N, van de Wetering M, van
den Born M, Begthel H, Vries RG, Stange DE,
Toftgård R, Clevers H. (2010) Lgr6 marks stem
cells in the hair follicle that generate all cell lineages of the skin. Science. 327(5971):1385-9.
Lauth M, Bergström A, Shimokawa T, Tostar U,
Jin Q, Fendrich V, Guerra C, Barbacid M, Toftgård R. (2010) DYRK1B-dependent autocrineto-paracrine shift of Hedgehog signaling by
mutant RAS. Nat Struct Mol Biol. 17(6):71825.
Ekaterina Morgunova
Kazuhiro Nitta
Bernhard Schmierer
Inderpreet Sur
Minna Taipale
Thomas Whitington
Jian Yan
Anna Zetterlund
Teglund S, Toftgård R. (2010) Hedgehog beyond
medulloblastoma and basal cell carcinoma.
Biochim Biophys Acta. 1805(2):181-208.
Network representation describing similarity of nuclear receptor DNA-binding specificities. Diamonds
indicate TF genes. Binding models derived from human full length TFs (large circles), DBDs (small circles)
and mouse DBDs (triangles) are also shown. Edges are drawn between a TF and corresponding models, and
between two models if they are similar. Computationally chosen representative models are indicated by
blue outline, and the representative model sequence logos are also shown. Most of the nuclear receptors
bind DNA as homodimers and different proteins vary both in the terms of the half-site sequence specificity
and allowed half site spacings and orientations.
30
Hedgehog signalling, tissue
stem cells and cancer
development
Picture of a part of a human hair follicle illustrating expression of the tissue stem cell markers SOX9 (red)
and LGR5 (green) in the outer root sheath keratinocytes. Positive staining for LGR5 is also seen in sebocytes.
Nuclei are counterstained in blue.
Group members
Agneta Andersson
Åsa Bergström
Leander Blaas
Yumei Diao
Mohammed
Ferdous-Ur Rahman
Csaba Finta
Marco Gerling
Karin Heby Henriksson
Maria Hölzl
Viljar Jaks
Åsa Jansson
Biljana Jovanovic
Jens Henrik Norum
Uta Rabenhorst
Fabian Schneider
Stephan Teglund
Elin Tüksammel
Victoria Villegas
Peter Zaphiropoulos
31
Eckardt Treuter
+46 8 524 810 60
[email protected]
ki.se/bionut/treuter
Toubal, A., Clément, K., Fan, R., Ancel, P., Pelloux, V., Rouault, C., Veyrie, N., Hartemann, A.,
Treuter, E. (shared corresponding author), and
Venteclef, N. (2012) SMRT-GPS2 corepressor
pathway dysregulation coincides with obesitylinked adipocyte inflammation. The Journal of
Clinical Investigation, Epub ahead of print.
Ehrlund A, Jonsson P, Vedin LL, Williams C,
Gustafsson JÅ, Treuter E. (2012) Knockdown
of SF-1 and RNF31 affects components of steroidogenesis, TGFβ, and Wnt/β-catenin signaling
in adrenocortical carcinoma cells. PLoS One
7:e32080.
Venteclef N, Jakobsson T, Steffensen KR,
Treuter E. (2011) Metabolic nuclear receptor
signaling and the inflammatory acute phase
response. Trends in Endocrinology and Metabolism 22:333-43.
Epigenomic control of
metaflammation by nuclear
receptor-coregulator pathways
Public health nutrition
We are interested in understanding the intricate relationship between metabolism and
inflammation, referred to as ‘metaflammation’,
which emerges as a key feature of the metabolic syndrome and its components obesity,
insulin resistance, and type 2-diabetes. Our
research is driven by the hypothesis that closely
linked metabolic and (anti-) inflammatory
nuclear receptor-coregulator pathways play
central roles in transcriptional and epigenomic
mechanisms of disease. Specifically, we suspect
that pathways involving the anti-inflammatory
mediator GPS2 function as a critical molecular
entry point for the integration of metabolic and
inflammatory signals.
The public health nutrition group is mostly
involved in the nutritional health of children
and infants. We have performed research on
breast milk composition, especially investigating fatty acid composition and polyamine
content related to the diet of the mother,
studied breastfeeding prevalence and duration
in relation to socio-demographic determinants
as well as studies on vitamin A and D status of
Iranian infants. In both animals and infants we
have studies long-term effects of early nutrition. Fruit and vegetable intake among 11-year
old children has been investigated in a selection of European countries. Data on overweight
prevalence in Swedish 7-8 year old children has
been studied in a population-representative
sample. We have also investigated nutritional
links to cognitive development in children and
revealed the most important polyamine sources
in the Swedish diet.
Anti-inflammatory GPS2 pathways
So far, we have identified three key features
of these pathways that appear highly diseaserelevant: (1) Control of nuclear receptor
cistromes (DNA binding) and epigenomes
(histone modifications) at certain genes, such
as the cholesterol transporter gene ABCG1.
(2) Crucial component of anti-inflammatory
transrepression by lipid-sensing nuclear
receptors such as LXRs. (3) Dysregulation of
an adipocyte-specific corepressor complex that
controls inflammation in human obesity. Overall, these findings suggest that nuclear receptorGPS2 pathways are directly involved in human
metaflammatory diseases and potentially can
be therapeutically modulated. Thus, our future
work will further dissect these disease mechanisms, using mouse models and translational
human studies, and also aim to develop novel
anti-inflammatory treatment strategies.
Another interest in the group is interventions
in regards to nutrition and physical activity,
with intervening on fruit and vegetable intake
in 11-year olds, a generally healthy lifestyle
in pregnant women and promoting physical
activity in an university staff.
The group is very active in European public
health nutrition research and has during the
last 15 years been coordinating eight EU funded projects, and is every year running a course
on how to apply for funding from the European
Commission, in collaboration with WHO European Region. The unit is also involved in the
development of the profession of public health
nutrition on European level, with a fifteen year
experience in developing training programmes
and policy.
Venteclef N, Jakobsson T, Ehrlund A, Damdimopoulos A, Mikkonen L, Ellis E,
Nilsson LM, Parini P, Jänne OA, Gustafsson JA,
Steffensen KR, Treuter E. (2010) GPS2-dependent corepressor/SUMO pathways govern antiinflammatory actions of LRH-1 and LXRbeta in
the hepatic acute phase response. Genes and
Development 24:381-95.
Group members
Anastasios Damdimopoulos
Anna Ehrlund
Rongrong Fan
Zhiqiang Huang
Saioa Goni
Ning Liang
32
Metaflammatory nuclear receptor-GPS2 pathways in physiology and disease: targets for therapeutic
intervention. Molecular mechanisms: SUMOylated receptors (NRs) repress transcription of inflammatory
genes (e.g. macrophage cytokine genes, liver acute phase genes) by docking to promoter-bound GPS2/
corepressor (CoR) complexes linked to histone deacetylation, thereby preventing activation in response
to inflammatory stimuli. SUMOylation is regulated by NR ligands and by intracellular signals in a dynamic,
reversible, and cell-type dependent manner. Metabolites, endocrine disrupters, drugs and inflammatory
signals may modulate the anti-inflammatory capacity of NRs. Physiological consequences and therapeutic
possibilities: Highlighted are established and suspected tissues and diseases where NR/GPS2 pathways
might occur. Envisaged are pharmacological approaches that selectively modulate NR-SUMOylation,
GPS2/CoR interactions, or directly GPS2, all presenting new concepts for developing anti-inflammatory
drugs to combat specific metaflammatory diseases.
Figurre: Nilsson TK, Yngve A, Böttiger AK, Hurtig-Wennlöf A, Sjöström M.
Treuter E, Venteclef N. (2011) Transcriptional control of metabolic and inflammatory
pathways by nuclear receptor SUMOylation.
Biochimica Biophysica Acta 1812:909-18.
High dietary folate intake is related to better school performance in a population sample of 15-year-old
Swedish adolescents. Pediatrics. 2011 Aug;128(2):358-65.
Agneta Yngve
+46 8 5248 1085
[email protected]
ki.se/bionut/yngve
Palsdottir V, Wickman A, Andersson N, Hezaveh R, Olsson B, Gabrielsson BG, Strandvik
B. (2011) Postnatal deficiency of essential fatty
acids in mice results in resistance to diet-induced
obesity and low plasma insulin during adulthood. Prostaglandins Leukot Essent Fatty
Acids 84(3-4):85-92.
Nilsson TK, Yngve A, Böttiger AK, HurtigWennlöf A, Sjöström M. (2011) High dietary
folate intake is related to better school performance in a population sample of 15-year-old
Swedish adolescents. Pediatrics 128(2):35865.
Ali MA, Poortvliet E, Strömberg R, Yngve A.
(2011) Polyamines: total daily intake in adolescents compared to the intake estimated from the
Swedish Nutrition Recommendation Objectified
(SNO). Food & Nutrition Research 55:5455.
Sjöberg A, Moraeus L, Yngve A, Poortvliet E,
Al-Ansari U, Lissner L. (2011) Overweight and
obesity in a representative sample of school
children – exploring the urban-rural gradient in
Sweden. Obesity Reviews 12(5):305-14.
Olang B, Naghavi M, Bastani D, Strandvik B,
Yngve A. (2011) Optimal vitamin A and suboptimal vitamin D status are common in Iranian
infants. Acta Paediatrica 100(3); 439-444.
Group members
Usama Al-Ansari
Bettina Ehrenblad
Leif Hambræus
Susanna Kugelberg
Christel Lynch
Eric Poortvliet
Jenny Rossen
Ali Soroush
Birgitta Strandvik
33
Bioinformatics and expression analysis,BEAa
Institutet
Center for high resolution
electron microscopy, EMka Institutet
Contact
Fredrik Fagerström-Billai
[email protected]
+46 8 524 835 43
+46 8 524 831 11
bea.ki.se
Contact
Hans Hebert
[email protected]
+46 8 524 810 93
ki.se/bionut
Preparing specimens for cryo electron microscopy.
The core facility for Bioinformatics and Expression Analysis, BEA, is a national genomic
service facility. BEA provides an extensive
repertoire of genomic technologies to ongoing
research projects principally at the Karolinska
Institute but also at other Swedish universities.
BEA offers services for genomic analysis based
on the Affymetrix, Agilent, Illumina and ABI
platforms for microarrays and qPCR. This includes gene expression and RNA splicing analysis, transcriptome and DNA-binding analysis,
epigenetic analysis including DNA-methylation
and miRNA analysis, genome wide SNP and
copy number variation analysis.
The services at BEA range from experimental planning and complete processing of all
samples and reagents to data analysis and bioinformatic support. Recent additions at BEA
include the Affymetrix GeneTitan automated
plate microarray system and a Biomek FXP
PCR robot which has improved throughput
34
and reduced the cost of microarray analyses.
BEA handles more than 160 different individual projects from approximately 80 different
research groups and PIs yearly. The number
of different types of analysis has continuously
increased and today BEA handles approximately 3500 samples and performs more than
2500 individual microarray hybridizations
yearly (2011-2012). The implementation of
new genomic analysis methods and services
are important goals. For the moment BEA is
introducing standardized services for ChIP
and RNA sequencing on the Illumina HiSeq
platform and establishing protocols for small
sample and single cell analysis. BEA is also
involved in education and organizes workshops
and advanced doctoral courses.
Group members /personnel
David Brodin
Karin Dahlman-Wright
Fredrik Fagerström-Billai
Susann Fält
Malin Liljebäck
Jessica Lindvall
Marika Rönnholm
The objective of the high resolution
electron microscopy, EM, core facility is to
provide a seamless facility for general EM, cryoEM and high resolution studies of biological
specimens. The equipment comprises mainly:
Three transmission electron microscopes, (one
120 kV with LaB6 filament and two field emission gun microscopes with 200 kV and 300 kV
accelerating voltage respectively) all equipped
with CCD cameras, preparation equipment for
cryo specimens including a plunge freezing
robot, dedicated computer hardware and
software. One lab manager of the EM group
has continued to take the responsibility of
the equipment on a daily basis ensuring that
ultimate availability and performance of the
facility is achieved. One lab manager is responsible for wet lab facilities including equipment
for protein purification, 2D crystallization
and EM specimen preparation. Two senior
researchers are providing expertise with regard
to processing of data.
Internal projects and collaborations
The EM-group (membrane proteins, 2D
crystallization, large complexes, nanoparticles),
The Garoff group (viruses), The Jovine group
(large complexes and 2D crystals).
Group members/personnel
Hans Hebert
Caroline Jegerschöld
Philip Koeck
Martin Lindahl
Pasi Purhonen
Examples of outside visitors/users
• Vironova AB, one day a week at a rate cover
all costs, drug carriers
• Lund University, from the Chemistry Center, large complexes
• Karolinska Institutet, MBB, membrane
proteins, 2D crystallization and large
complexes
• Umeå University, virus structure
• University of Rome/Tor Vergata, micro and
nanoparticles
• Århus University, large complexes
35
Contact
Sylvie Le Guyader
[email protected]
+ 46 73 733 5008
ki.se/corefacilities
Karolinska high throughput center, KHTC
nska Institutet
Image: Ting Zhuang.
The live cell imaging unit, LCInska Institutet
Contact
Jianping Liu
+46 8 585 866 58
[email protected]
khtc.ki.se
Mouse mammary gland labelled with Carmine, imaged in 3D with the Andor spinning disk
microscope.
Overview of the integrated instruments at KHTC.
Microscopy is becoming increasingly important for the life sciences. The Live Cell Imaging (LCI) unit at BioNut offers its researchers
a unique set of microscopy tools as well as
expertise and advanced training. The Live Cell
Imaging unit provides a variety of confocal
microscopes, all fully automated and fully
equipped for live cell imaging. Collectively,
these microscopes allow applications as varied
as fast confocal imaging (resonant scanner,
spinning disk), spectral imaging, two-photon
microscopy, and fluorescence lifetime microscopy. Three workstations are also available
with all offline software as well as software for
automated image analysis in 5 dimensions
(xyz, time, colour). The LCI unit has more than
50 active users.
Sylvie Le Guyader
Staffan Strömblad
36
Karolinska high throughput center, KHTC, is
one of the most sophisticated, state-of-the-art
liquid handling and analytical platforms in
Europe. KHTC provides for scientific community instrumentation, reagents, methods and
know-how for systems biology and advanced
genomics. KHTC is a self-service facility
with a fee-for-use. We can assist with assay
development and robotics; however there is
no retention of intellectual property and full
confidentiality is guaranteed.
The live cell imaging unit offers its researchers a unique set of microscopy tools as well as
expertise and advanced training.
The instruments available at KHTC includes:
highly integrated laboratory automation workstations, advanced liquid handling robots, fully
automated microscope, Acumen eX3 High
Content Imaging System, high-throughput
PCR instrument, SELEX platform, Illumina
HiSeq2000 DNA sequencers, recombinant
DNA cloning/colony picking platform and
high-throughput yeast replicator. In addition, KHTC centrally manages collections
of genome-wide siRNA & ORF libraries and
several comprehensive chemical compound
libraries of >92,000 small molecules.
Jianping Liu
Thirupathi Pattipaka
Jussi Taipale
Minna Taipale
At KHTC we are capable of performing large
scale genetic screens (cDNA and RNAi) and
compound screens in various cellular and
biochemical assays, systematic evolution of
ligands by exponential enrichment (SELEX),
multiplexing by DNA barcoding and massively
parallel PCR. In 2012, two compound screens
were carried out, a RNA extraction method
was automated and three siRNA pre-screens
are in progress. In addition, four siRNA
screens, one cDNA screen and three compound screens have been initiated.
37
Examples of high impact publications
Siu MK, Chan HY, Kong DS, Wong ES, Wong
OG, Ngan HY, Tam KF, Zhang H, Li Z, Chan
QK, Tsao SW, Strömblad S, Cheung AN. (2010)
p21-activated kinase 4 regulates ovarian cancer
cell proliferation, migration, and invasion and
contributes to poor prognosis in patients. Proc
Natl Acad Sci U S A. 107(43):18622-7.
Teglund S, Toftgård R. (2010) Hedgehog beyond
medulloblastoma and basal cell carcinoma.
Biochim Biophys Acta. 1805(2):181-208.
Durand-Dubief M, Persson J, Norman U,
Hartsuiker E, Ekwall K. (2010) Topoisomerase
I regulates open chromatin and controls gene
expression in vivo. EMBO J. 29(13):2126-34.
2010
Han L, Monné M, Okumura H, Schwend T,
Cherry AL, Flot D, Matsuda T, Jovine L. (2010)
Insights into egg coat assembly and egg-sperm
interaction from the X-ray structure of fulllength ZP3. Cell,143(3):404-15.
Jolma A, Kivioja T, Toivonen J, Cheng L, Wei
G, Enge M, Taipale M, Vaquerizas JM, Yan
J, Sillanpää MJ, Bonke M, Palin K, Talukder
S, Hughes TR, Luscombe NM, Ukkonen E,
Taipale J. (2010) Multiplexed massively parallel
SELEX for characterization of human transcription factor binding specificities. Genome Res.
20(6):861-73.
Burroughs AM, Ando Y, de Hoon MJ, Tomaru
Y, Nishibu T, Ukekawa R, Funakoshi T, Kurokawa T, Suzuki H, Hayashizaki Y, Daub CO.
(2010) A comprehensive survey of 3' animal
miRNA modification events and a possible role
for 3' adenylation in modulating miRNA targeting effectiveness. Genome Res. 20(10):1398410.
Lauth M, Bergström A, Shimokawa T, Tostar
U, Jin Q, Fendrich V, Guerra C, Barbacid
M, Toftgård R. (2010) DYRK1B-dependent
autocrine-to-paracrine shift of Hedgehog
signaling by mutant RAS. Nat Struct Mol Biol.
17(6):718-25.
38
Morgunova E, Illarionov B, Saller S, Popov A,
Sambaiah T, Bacher A, Cushman M, Fischer
M, Ladenstein R. (2010) Structural study and
thermodynamic characterization of inhibitor
binding to lumazine synthase from Bacillus anthracis. Acta Crystallogr D Biol Crystallogr.
66(Pt 9):1001-11.
Camilleri M, Carlson P, Zinsmeister AR,
McKinzie S, Busciglio I, Burton D, Zucchelli
M, D'Amato M. (2010) Neuropeptide S receptor
induces neuropeptide expression and associates
with intermediate phenotypes of functional
gastrointestinal disorders. Gastroenterology.
138(1):98-107.e4.
Venteclef N, Jakobsson T, Ehrlund A, Damdimopoulos A, Mikkonen L, Ellis E, Nilsson
LM, Parini P, Jänne OA, Gustafsson JA, Steffensen KR, Treuter E. (2010) GPS2-dependent
corepressor/SUMO pathways govern antiinflammatory actions of LRH-1 and LXRbeta
in the hepatic acute phase response. Genes Dev.
24(4):381-95.
Murtola M, Wenska M, Strömberg R. (2010)
PNAzymes that are artificial RNA restriction
enzymes. J Am Chem Soc. 132(26):8984-90.
Fan X, Gabbi C, Kim HJ, Cheng G, Andersson
LC, Warner M, Gustafsson JA. (2010) Gonadotropin-positive pituitary tumors accompanied by
ovarian tumors in aging female ERbeta-/- mice.
Proc Natl Acad Sci U S A. 107(14):6453-8.
Tan XJ, Fan XT, Kim HJ, Butler R, Webb P,
Warner M, Gustafsson JA. (2010) Liver X receptor beta and thyroid hormone receptor alpha in
brain cortical layering. Proc Natl Acad Sci U S
A. 107(27):12305-10.
Piasecki BP, Burghoorn J, Swoboda P. (2010)
Regulatory Factor X (RFX)-mediated transcriptional rewiring of ciliary genes in animals. Proc
Natl Acad Sci U S A. 107(29):12969-74.
Gabbi C, Kim HJ, Barros R, Korach-Andrè M,
Warner M, Gustafsson JA. (2010) Estrogendependent gallbladder carcinogenesis in LXRbeta-/- female mice. Proc Natl Acad Sci U S A.
107(33):14763-8.
Wu SR, Löving R, Lindqvist B, Hebert H,
Koeck PJ, Sjöberg M, Garoff H. (2010) Singleparticle cryoelectron microscopy analysis reveals
the HIV-1 spike as a tripod structure. Proc Natl
Acad Sci U S A. 107(44):18844-9.
Wei GH, Badis G, Berger MF, Kivioja T, Palin
K, Enge M, Bonke M, Jolma A, Varjosalo M,
Gehrke AR, Yan J, Talukder S, Turunen M, Taipale M, Stunnenberg HG, Ukkonen E, Hughes
TR, Bulyk ML, Taipale J. (2010) Genome-wide
analysis of ETS-family DNA-binding in vitro and
in vivo. EMBO J. 29(13):2147-60.
2011
Thomas C, Gustafsson JÅ. (2011) The different roles of ER subtypes in cancer biology and
therapy. Nat Rev Cancer. 11(8):597-608.
Nilsson S, Koehler KF, Gustafsson JÅ. (2011)
Development of subtype-selective oestrogen
receptor-based therapeutics. Nat Rev Drug
Discov. 10(10):778-92.
Barros RP, Gustafsson JÅ. (2011) Estrogen receptors and the metabolic network. Cell Metab.
14(3):289-99.
Zucchelli M, Camilleri M, Andreasson AN,
Bresso F, Dlugosz A, Halfvarson J, Törkvist L,
Schmidt PT, Karling P, Ohlsson B, Duerr RH,
Simren M, Lindberg G, Agreus L, Carlson P,
Zinsmeister AR, D'Amato M. (2011) Association of TNFSF15 polymorphism with irritable
bowel syndrome. Gut. 60(12):1671-7.
Korach-André M, Archer A, Barros RP, Parini
P, Gustafsson JÅ. (2011) Both liver-X receptor
(LXR) isoforms control energy expenditure by
regulating brown adipose tissue activity. Proc
Natl Acad Sci U S A. 108(1):403-8.
Butler R, Inzunza J, Suzuki H, Fujii-Kuriyama
Y, Warner M, Gustafsson JÅ. (2012) Uric acid
stones in the urinary bladder of aryl hydrocarbon receptor (AhR) knockout mice. Proc Natl
Acad Sci U S A. 109(4):1122-6.
Kasper M, Jaks V, Are A, Bergström Å, Schwäger A, Svärd J, Teglund S, Barker N, Toftgård R.
(2011) Wounding enhances epidermal tumorigenesis by recruiting hair follicle keratinocytes.
Proc Natl Acad Sci U S A. 108(10):4099-104.
Gabbi C, Kong X, Suzuki H, Kim HJ, Gao M,
Jia X, Ohnishi H, Ueta Y, Warner M, Guan Y,
Gustafsson JÅ. (2012) Central diabetes insipidus
associated with impaired renal aquaporin-1 expression in mice lacking liver X receptor β. Proc
Natl Acad Sci U S A. 109(8):3030-4.
Muthusamy S, Andersson S, Kim HJ, Butler R,
Waage L, Bergerheim U, Gustafsson JÅ. (2011)
Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway
that is lost in prostate cancer. Proc Natl Acad
Sci U S A. 108(50):20090-4.
Yakimchuk K, Iravani M, Hasni MS, Rhönnstad
P, Nilsson S, Jondal M, Okret S. (2011) Effect of
ligand-activated estrogen receptor β on lymphoma growth in vitro and in vivo. Leukemia.
25(7):1103-10.
Löving R, Wu SR, Sjöberg M, Lindqvist B,
Garoff H. (2012) Maturation cleavage of the
murine leukemia virus Env precursor separates
the transmembrane subunits to prime it for
receptor triggering. Proc Natl Acad Sci U S A.
109(20):7735-40.
2012
Sur IK, Hallikas O, Vähärautio A, Yan J, Turunen M, Enge M, Taipale M, Karhu A, Aaltonen LA, Taipale J. (2012) Mice lacking a Myc
enhancer that includes human SNP rs6983267
are resistant to intestinal tumors. Science.
338(6112):1360-3.
Kivioja T, Vähärautio A, Karlsson K, Bonke M,
Enge M, Linnarsson S, Taipale J. (2012) Counting absolute numbers of molecules using unique
molecular identifiers. Nat Methods. 9(1):72-4.
Kasper M, Jaks V, Hohl D, Toftgård R. (2012)
Basal cell carcinoma - molecular biology and potential new therapies. J Clin Invest. (2):455-63.
Jakobsson T, Treuter E, Gustafsson JÅ, Steffensen KR. (2012) Liver X receptor biology
and pharmacology: new pathways, challenges
and opportunities. Trends Pharmacol Sci.
33(7):394-404.
39
Dissertations 2010-2012 ska Institutet
2011
Ulrica Tostar, Hedgehog Signaling in Rhabdomyosarcoma: Role of GLI Factors and
Splice Variants in Signal Transduction
Gayathri Chandrasekar, Zebrafish as a Model to Study the Neuroendocrine System and
Toxicity of Endocrine Disruptors
Anna Ehrlund, Transcriptional Regulation by
the Nuclear Receptors Steroidogenic Factor-1
and Liver Receptor Homologue-1
Beheshteh Olang, Aspects of Feeding Patterns in the First Two Years of Life in Iranian
Infants
Chiara Gabbi, Studies on the Oxysterol Receptor LXRbeta Linking Cholesterol metabolism to water transport and cell proliferation
Ylva Rosengardten, Development of a
Mouse Model for Hutchinson-Gilford Progeria Syndrome Reveal Defects in Adult Stem
Cell Maintenance
Juan Carlos Fierro-Gonzalez, The Plasticity
of Aging and Survival: A Role for Thioredoxin
System in Caenorhabditis Elegans
40
Eva Schmidt, Mouse Models for Understanding the Molecular Mechanism of Bone
Disease in Hutchinson-Gilford Progeria
Syndrome
Marina Ezcurra, Feeding State Modulates
Nociception in Caenorhabditis Elegans
Kirsi Harila, VPU-Mediated Intracellular Targeting of HIV-1 Core Protein Precursor PR55
GAG and Association of PR55 GAG with Lipid
Microdomains
Kristiina Tammimies, Molecular Studies
of Dyslexia – Regulation and Function of
DYX1C1
Karin Heby-Henricsson, The Role of Suppressor of Fused in Development and Tumorigenesis in the Mouse
Mohamed Ali, Polyamines in Foods and
Human Milk
Karin Edvardsson, Exploring the GenomeWide Impact of Estrogen Receptor Alpha and
Estrogen Receptor Beta in Breast and Colon
Cancer Cells
2012
2010
Indranil Sinha, Genome-Wide Patterns of
Histone Modifications in Fission Yeast
Hanna Peterson, Genetic Studies of PreEclampsia
Emma Patterson, Dietary Intakes of Swedish
Children and Adolescents
Zhengwen An, Integrin-Interacting Proteins
in Human Cancer Progression
Katarina Hart, Molecular Dynamics Simulations of Protein-Nucleic Acid Complexes
Tiina Järvinen, Genetic Studies on Finnish
Lupus Erythematosus Patients with Cutaneous Manifestations
Chiounan Shiue, Role of c-Myc in the
Regulation of rDNA Transcription by RNA
Polymerase I
Carolina Bonilla (lic examen), Studies of
Histone Modification Systems in Schizosaccharomyces Pombe
Gilbert Lauter, Characterization of Evolutionary Conserved Subdivisions in the Embryonic Zebrafish Forebrain Based on Gene
Expression Patterns
Christina Orsmark-Pietras, Interaction and
Regulation of Asthma Susceptibility Genes
Robin Löving, Activation of Retrovirus Spikes
for Membrane Fusion
Tomas Jakobsson, Oxysterol Receptors LXRs
and Coregulators in Cholesterol Metabolism
and Inflammatory Transrepression Pathways
Lena Hallström, Breakfast Habits among
European Adolescents – The Healthy Lifestyle
in Europe by Nutrition in Adolescence (HELENA) study
Birgitta Pettersson, Synthetic Studies
towards 7-and 8-Membered N-heterocycles,
Particularly 1,4-Pyrrolobenzodiazepines –
Total synthesis of Fuligocandin A and B
Clara Ersson, International Validation of the
Comet Assay and a Human Intervention Study
Marianna Wirén, Genome-Wide Study of
HDACs and Transcription in Schizosaccharomyces Pombe
Yong-Guang Tong, Regulatory Function of
Homeobox Genes in the Development of C.
Elegans
Erik Flöistrup (lic examen), Synthesis of Estradiol Mimetics and anti-Alzheimers Agents
Zhilun Li, Role of p21-Activated Kinase 4 in
Cell Migration
Karina Gheorge, Persistent Inflammatory
Pathways in Rheumatoid Arthritis Despite
Anti-rheumatic Treatment
Karolina Lindberg, Estrogen Receptor beta
Signalling in Mammary Epithelial and Breast
Cancer Cells
Wen Cai, ER subtype-specific regulation of
estrogen signaling
Ylva Rodhe, (lic examen) Assessment of DNA
Damage, Oxidative Stress and Inflammation
in Chronic Kidney disease patients- and a
clinical study of a dietary supplement
Krishan Johansson Haque, Molecular
mechanisms of Glucocorticoids: Anti-inflammatory implications
Johan Henriksson, Spatio-temporal modeling of morphology and gene-expressions
during C. elegans embryogenesis using a new
imaging framework
Lars Braeutigam, Urocortins in the zebrafish
brain and redox regulation of embryonic
development through Glutaredoxins
Milica Putnik, Molecular characterization
of estrogen receptors with focus on breast
cancer
Olof Allnér, Biomolecular Simulations, from
RNA to Protein: Thermodynamic and Dynamic Aspects
Nina Gustafsson Shepard, Modulation of
Nuclear Receptors Signaling by RBR Ubiquitin
Ligases
Jingwen Shi, Biocompatibility of synthetic
nanomaterials and their applications in gene
delivery
Pontus Cronholm, Toxicity of metal and
metal oxide nanoparticles. The importance
of physicochemical properties and cellular
uptake.
Stefan Ek, Nitro compounds for use in explosive charges
Therese Woodhill, The Paradox of Micronutrients – In vitro and human studies
Annelie Strålfors, Chromatin remodelers
and their roles in chromatin organization.
41
Undergraduate teaching nstitutet
Contact
Sam Okret
+46 8 524 81069
[email protected]
in Nutrition are the only Swedish academic
educations with nutrition as their major.
The bachelor program deals with nutrition
from many different perspectives - medical,
biochemical, molecular, epidemiological and
public health perspectives. Evidence based
relationships between food and health are
main topics. It differs from “Dietician education" as the students obtain a deep knowledge
in natural sciences, including chemistry (45
credits), cell biology (30 credits), physiology
and molecular nutrition. The broad profile
of the program gives the students a lot of
possible professional roles to choose between
after completing their training. Among other
things, they work with health education,
health administration or development of new
consumer products.
The master program in Nutrition is based on
the bachelor program and offers additional
research interaction and possibilities to go
At the Department of Biosciences and Nutrition research and education go hand in hand.
Although research constitutes the larger part of
the Department’s activities, education is an important and central part of the department’s activities. This is exemplified by the participation
of the Departmental Educational Coordinator
in the Departmental management group.
The Department has its main competence in
basic biosciences and nutrition and it is also
within these educational areas the department
is mainly involved. Our goal is that all our
educational activities are scientifically based
and closely connected to ongoing research.
Furthermore, we think that education is an important way to communicate the latest scientific standpoints so that students completing the
courses or programs given by the Department
become knowledgeable, skilled and trustworthy professionals with high credibility within
their respective educational areas.
The Department of Biosciences and Nutrition’s
main educational engagements are within the
bachelor and master’s programs in Biomedi-
42
cine and bachelor and master’s program in
Nutrition, the latter of which the Department
gives in collaboration with Stockholm University. The Department has the overall responsibility for the bachelor and master’s programs
in Nutrition. In addition, the Department gives
freestanding courses in Public Health Nutrition
at Karolinska Institutet. Teachers at the Department also participate in teaching activities at
other programs at the Karolinska Institutet e.g.
the Medicine program with lectures/seminars
in Public Health and Environmental Medicine
and Nutrition.
Within the Biomedicine program the Department is responsible for several courses both at
the bachelor and masters level comprising a
total of 58 credits (10 at the bachelor level, 48
at the master’s level) with 44 annual performance equivalents (HÅP). For the 3 year bachelor program in Nutrition, the Department
is responsible for courses corresponding to
105 credits and for 90-120 credits (depending
on the length of the degree project) on the
master’s program in Nutrition. All together
both deeper and broader into studying questions related to food and health. The master’s
program also includes courses in communication, philosophy of science, pedagogics and
environmental aspects on food production
and consumption. The bachelor and master’s
program in Nutrition had during the autumn
of 2012 to write a “self evaluation” report
as part of the Swedish National Agency of
Higher Education ongoing evaluation of all
national university programs.
Finally, the Department works hard to develop the pedagogical skills of the departmental
teachers by offering seminars in pedagogical
techniques. Furthermore, a role for an Educational Cooordinator working with coordination and pedagogical training is in place.
Examples of freestanding courses given are
“Behavior change in nutrition and physical
activity”, “Public health Nutrition within the
EU” and “Basic Nutritional Physiology”.
Some courses on the postgraduate program
given by the department are also offered
as elective courses to the undergraduate
students, e.g. in bioinformatics and nuclear
receptors and metabolism.
this corresponds to 58 annual full time student
equivalents (HÅS) and 55 total annual performance equivalents in the bachelor and masters
programs in Nutrition. Generally, the courses
at the bachelor’s level given at the Department
are taught in Swedish while all courses at the
master’s level given at the Department are
taught in English.
Courses given at the bachelor level within the
Biomedicine program include “Cell Biology
and Genetics”. At the masters program in
Biomedicine, they include courses in Applied
Communication in Biomedicine where the
students learn how to communicate science
in speech and writing to colleagues, the media
and to the public and how to write grant applications. The courses also include philosophy
of science and bioethics. The Department is
also responsible for the Degree projects at the
master’s programs in Biomedicine.
The education in Nutrition in collaboration
with Stockholm University was initiated more
than 40 years ago. The education programs
43
Networks a Institutet
Awards nska Institutet
Examples of scientific networks
that scientists at the Department of Biosciences and Nutrition participated in 2010-2012.
NetworkWeb siteResearcher
EU FP6- & FP7-FOOD NoE: ECNIS and ECNIS2
ecnis.org
Lennart Möller, Jospeh Rafter, Dan Segerbäck
EU FP7-HEALTH NoE Collaborative project SYSCOL
syscol-project.eu
Jussi Taipale (coordinator)
EU FP7-HEALTH NoE: Systems Microscopy
systemsmicroscopy.eu
Staffan Strömblad (coordinator)
EU FP7-ENVIRONMENT FRP: ICEPURE
icepure.eu
Dan Segerbäck
EU FP7-HEALTH FRP: MAARS maars.eu
Juha Kere
EU FP6-FOOD IP: NewGeneris
newgeneris.org
Dan Segerbäck
EU FP7-FOOD IP: TORNADO
fp7tornado.eu
Joseph Rafter (vice coordinator)
EU FP7-HEALTH IP: TOLERAGE
tolerage.eu
Sam Okret
EU FP7-PEOPLE-ITN: Virus Entry
2.hu-berlin.de
Henrik Garoff
EU FP7-PEOPLE-ITN: Healing
fp7-healing.eu
Maria Kasper, Rune Toftgård
EU-ITN PhosChemRec Roger Strömberg
EuroNanoMed (EU/VR) NanoSpliceRoger Strömberg
FANTOM consortium
fantom.gsc.riken.jp
Carsten Daub, Karl Ekwall, Juha Kere
StratCan ki.se/stratcanRune Toftgård (director), Jussi Taipale
BRECT ki.seStaffan Strömblad (co-director), Rune Toftgård
The Strategic Research Programme in Diabetes
ki.se/srp-diabetes
Karin Dahlman-Wright, Juha Kere
ESF-network ”SimBioMa” 2010-2011
esf.org
Lennart Nilsson (member of steering committee)
IIBDGCibdgenetics.orgMauro D’Amato (Management Committee)
GENIEUR genieur.eu
Mauro D’Amato (WG3 Management Committee)
SOIBDMauro D’Amato
NORGEN norgen.ki.se
Karin Dahlman-Wright, Jan-Åke Gustafsson, Eckardt Treuter
NordForsk C. elegans Shared Technology Platforms
nordiccelegans.org
Thomas Bürglin, Peter Swoboda
NordForsk Cilia and Centrosome
nordiccilia.org
Peter Swoboda (co-funder)
NordForsk Chromatin, Transcription and Cancer
nordforsk.org
Karl Ekwall
NordForsk Non-coding RNAnordforsk.orgKarl Ekwall
NEONneon.sahlgrenska.gu.se
Marie Löf
NCycle – The Network of Nutrition during the Reproductive Cycle Marie Löf
The Swedish Research Council research network in Epigenetics
Karl Ekwall (Founder and Chairman)
Epigenetiska mekanismer i astma och allergi (supported by SSF)
Juha Kere
Stockholm Particle GroupLennart Möller
44
Awards and prizes awarded to scientists at the Department of Biosciences
and Nutrition 2010-2012.
Carsten Daub
RIKEN OSC Award “Successful Completion of FANTOM4 project” (2010).
Karl Ekwall
Distinguished Professor Award Karolinska institutet (2010-2014).
Gene Expression Systems Epigenomics Innovator Award (2011).
Maria Eriksson
VINNMER fellow – Marie Curie international qualification from VINNOVA (2012-2015).
Innovator Award from The Progeria Research Foundation (2012-2013).
Jan-Åke Gustafsson Molecular and Cellular Oncology, the University of Texas, M.D. Anderson Cancer Center, Houston, Texas (2010).
The Grand Silver Medal of Karolinska Institutet (2011).
Honorary Doctor in Medicine, University of Turku, Turku, Finland (2011).
Luca Jovine
ERC Starting Grant (2010).
EMBO Young Investigator Award (2010).
Göran Gustafsson Prize in Chemistry (2012).
Erik K. Fernström Prize (2011).
Sven och Ebba-Christina Hagberg Prize for Medical Research (2011).
Maria Kasper
Ragnar Söderberg Fellow in Medicine, Sweden (2012).
Cancerfonden Young Investigator Award, Sweden (2012).
Jürgen Schweizer Prize, European Hair Research Society, Israel (2011).
Juha Kere Distinguished Professor Award at Karolinska Institutet (2010-2014).
Matti Äyräpää price of medicine, awarded by the Finnish Medical Society Duodecim (2011).
Michael Sjöström
Medal from the University of Granada for strong academic and scientific leadership in the EU funded HELENA project and “The European Youth Heart Study”
Jussi Taipale
Erik K. Fernströms Prize for young researchers (2010).
Göran Gustafssons Prize in molecular biology (2011).
Awarded Lifelong EMBO Membership (2011).
Rune Toftgård
Distinguished Professor Award at KI (2010).
Elected Member of the Nobel Committee at KI (2010-2012).
45
The department in brief ska Institutet
INCOME STATEMENT
2010
2011
2012
Revenues from grants
Revenues from fees
Revenues from allowances
Internal revenues
65 340
12 807
165 967
8 167
65 189
9 020
157 107
10 611
57 127
11 302
158 949
15 872
Total revenues
252 281
241 927
Key financial figures
External / total financing
74%
73%
Research & doctoral education
94%
95%
First and second level education
6%
5%
243 250
77%
94%
6%
Doctoral students
2010
BioNut had 70 registrered doctoral students. 13 PhD-students were registrered, 11 held their
doctoral thesis defence and 2 students got a licentiate degree.
2011
BioNut had 61 registrered doctoral students. 7 PhD-students were registered, 21 held their
doctoral thesis defence.
2012
BioNut had 55 registrered docoral students. 8 PhD-students were registered, 12 held their
doctoral thesis defence and 2 students got a licentiate degree.
46
47
Organizationska Institutet
Contactnska Institutet
The Department of Biosciences and
Nutrition is situated at the NOVUM
research park in Huddinge, adjacent
to Karolinska University Hospital in
Huddinge.
Head of Department
1st and 2nd level
bachelor/master
Department council
Education
Collaboration group
Work environment group
3rd level doctoral
education
Special assignments
Administration
Research groups
Core facilities
Mailing address
BEA
EM
Bürglin
DahlmanWright
KHTC
LCI
Garoff
Gustafsson
Hebert
Jovine
Kasper
Kere
Löf
Möller
Nilsson
Okret
Rafter
Sjöström
Segerbäck
Strömberg
Strömblad
Swoboda
Taipale
Toftgård
Treuter
Yngve
Daub
D’Amato
Ekwall
Eriksson
Economy
Personnel
Labservice
Researcher
service
The Department of Biosciences and Nutrition
Novum
141 83 Huddinge
Sweden
Visiting address
Blickagången 6 or
Hälsovägen 7 (by car)
141 57 Huddinge
Home page
ki.se/bionut
Public transport
Bus: To and from central Stockholm as well as
interconnections with the underground system. Routes and time tables, see www.sl.se
Metro: 15 minutes from Stockholm Central by
commuter trains to Flemingsberg/Stockholm
Syd Station: use the south exit. Walk towards
Karolinska University Hospital (Huddinge).
You can not miss the NOVUM building on
your right hand side. Routes and time tables,
see www.sl.se
By car
Drive from Stockholm to Novum Research
Park, Hälsovägen 7: E4 southwards, turn off at
Vårby (exit 148), follow the hospital signs to
Karolinska University Hospital in Huddinge
and Novum Research Park. Guest parking
outside the main entrance, first exit after the
Hospital.
Switchboard
+46 8 524 800 00
48
49
ki.se
Karolinska Institutet
Communications and Public Relations Office | Text: The Department of Biosciences and Nutrition
Photo: Fredrik Hjerling, Björn Grevsten, Istock Photo, Karolinska Institutet, Staffan Larsson and Anders Lindholm
Print: Kaigan | ISBN: 978-91-85681-54-9

The Department of Biosciences and Nutrition

Transcription

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