Judith Staerk group

Background:

Our research team is generally interested in understanding molecular processes during normal and malignant hematopoiesis. Hematopoiesis describes the formation of all blood cells throughout life. This is ensured by long-term repopulating hematopoietic stem cells (HSC) that give rise to HSC and progenitors with limited renewing capacity. These progenitors produce lineage specific daughter cells that in turn form terminally differentiated erythroid/myeloid and lymphoid cell types. HSC division and blood cell differentiation is tightly regulated by genetics and epigenetic events as well as activation of specific signaling pathways. The dysregulation of one or more of these biological processes can lead to various blood disorders such as leukemia.

 

             

Figure 1: Overview of general approaches and methodologies used in my group. The broad research aim of my group is to identify key molecular processes that govern hematopoietic specification, hematopoietic stem cell renewal and differentiation, and differentiation of blood progenitors into mature blood cells. We are using primary patient samples, patient-derived iPSC, genetically modified hESC lines encoding reporter genes to monitor mesoderm and blood differentiation as well as in vivo zebrafish and mouse models.

 

Research in the Staerk group aims to decipher molecular processes that govern normal and malignant hematopoiesis and focuses on: i) identifying epigenetic and genetic events and signaling pathways that are crucial for human blood development, ii) deciphering the mechanisms by which the nuclear lamina influences hematopoietic development, and iii) identify underlying molecular causes of myeloid blood disorders triggered by defects in lineage differentiation that we study in the physiologic setting. To achieve these goals, we are using human pluripotent stem cells, in vitro differentiation assays as well as animal models along with primary patient samples and we combine these assays with genetic and genomic approaches. Insight obtained from our research projects will help to identify factors needed for efficient blood cell differentiation, and how this differentiation is affected in disease. Further, it will help to identify factors needed to expand functional HSC isolated from bone marrow (BM), and to derive functional HSC from pluripotent stem cells in vitro.

 

Epigenetic changes during human blood development

One main focus of my group is to understand how epigenetic signatures influence cell fate determination during mesoderm and hematopoietic cell specification. DNA methylation is an epigenetic modification which is key to numerous processes including regulation of gene expression and maintaining genomic integrity. Additional complexity to the overall gene regulation has been added by the discovery of Ten-Eleven-Translocation (TET) enzymes, which are dioxygenases that catalyze the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). The general importance of 5mC and 5hmC during development has been documented in animal models. Recently, we characterized 5hmC distribution in CD34+ cells and mature blood lineage cells and showed that in CD34+ cells, 5hmC primes expression of genes that regulate myeloid and lymphoid lineage commitment. Throughout blood cell differentiation, intragenic 5hmC is maintained at genes that are highly expressed and required for acquisition of the mature blood cell phenotype. Moreover, in CD34+ cells, 5hmC at enhancers was associated with increased binding of RUNX1 and FLI1 that are TFs crucial for hematopoiesis. To further investigate the role of 5mC and 5hmC during human blood cell differentiation, we now established oxidative bisulfite sequencing and deleted endogenous DNMT3A and 3B or different TET family members in hESC lines encoding reporter genes that allow monitoring blood cell differentiation. We aim to decipher how epigenetic changes and transcriptional networks interact during blood cell formation, and how 5mC as well as 5hmC influence the recruitment of key TFs during human hematopoiesis. Critical to this question is how epigenetic modifiers such as DNMT and TET enzymes interact with non-coding-RNAs (nc-RNAs) and which nc-RNA networks are required to generate mesoderm and hematopoietic progenitor cells from hESC.

 

Role of the nuclear lamina during human hematopoiesis

More recently, the group developed an interest in the nuclear lamina (NL)/lamin proteins. Lamins are divided into A-type lamins that are expressed in most somatic cell types, but are not expressed in stem cells, while B-type lamins (LMNB1 and LMNB2) are highly expressed in both, stem cells and differentiated cell types. Apart from the well-established role in forming a scaffold underneath the inner nuclear membrane, the NL has been implicated in nuclear positioning of chromatin and transcriptional regulation, which is thought to be critical for cell fate decisions. We aim to address how lamin-mediated gene regulation influences human hematopoiesis, and whether lamin proteins are dysregulated in blood disorders. Lamin proteins tether chromatin to the NE and influence transcription, signaling networks and cell fate decisions. Deciphering lamin-mediated gene regulation during blood cell specification will increase our understanding of underlying regulatory mechanisms during blood cell differentiation in the physiologic setting and will help to elucidate whether these processes are affected in disease.

 

Group members: 

Marie Rogne, Researcher

Theresa Ahrens, Postdoc

Safak Caglayan, Postdoc

Artur Ciesla-Pobuda, Postdoc

Adnan Hashim, Postdoc

Julia Madsen-Østerbye, PhD student

Oksana Svärd, PhD student

Kirsti Præsteng, Engineer

 

 

 

 

Gareth Sullivan group

 

Background

Current models employed by the pharmaceutical industry and academia to investigate disease, drug discovery/ safety/ efficacy, and toxicity are inadequate, as they do not faithfully recapitulate the human physiology, metabolism or cellular behavior. Consequently, there is a pressing need to improve this. The development of human induced pluripotent stem cell (hiPSC) technology, provides a novel way to model human disease and offers an alternative to current cell-based systems, most importantly as a potentially limitless supply of genetically defined stem cells that can be differentiated into virtually any cell type under defined conditions. This approach decreases dependency, usage and the overall numbers of animal models, in compliance with the 3R's (Reduction, Refinement and Replacement). Current hiPSC technology itself has its own limitations, which include lack of differentiation procedures to many cell types required combined with an immature phenotype of derived somatic progeny. We are addressing these shortcomings by investigating a number of key areas listed below. This will allow the potential use of the derived hiPSCs and their progeny in disease modeling, toxicity studies, drug discovery/ safety/ efficacy and in the long term, potential therapeutic application.

 

Research goal

The long-term goal of our work is to improve current methods of reprogramming  and transdifferentiation while gaining insight into the mechanistic processes involved.  In addition we will utilize these technologies to derive disease specific models to investigate disease processes in the dish.  To reach these goals, we are (ii) establishing methods of transdifferentiation, (ii) improving current methodologies of differentiation towards endoderm and other lineages, and (iii) applying these to disease models.

 

Current Projects 

 I. Nuclear reprogramming and changing cell fate – Transdifferentiation.

 II. Understanding differentiation.

 III. The use of small molecules for the derivation of hepatic cell types from human pluripotent stem cells.

 IV. 3D culture systems to develop physiologically relevent tissue models

 V. Disease modelling

 VI. Conservation of critically endangered species 

 

Selected publications (2010-2017):

Siller R, Dufour E, Wilmut I, Jung Y-W, Park IH and Sullivan GJ*. Development of an inducible platform for intercellular protein delivery.International Journal of Pharmaceutics.2017: http://dx.doi.org/10.1016/j.ijpharm.2017.02.067. (*corresponding).

Gamal W, Treskes P, Chesne CG, Samuel K, Sullivan GJ, Siller R, Srsen V, Underwood I, Smith S, Hayes PC, Plevris JN, Bagnaninchi PO and Nelson LJ. Low-dose acetaminophen induces early disruption of cell-cell tight junctions in human hepatic cells and mouse liver. Scientific Reports.2017:DOI: 10.1038/srep37541.

Siller R, Naumovska E, Mathapati S, Lycke M and Sullivan GJ*. Development of a rapid screen for the endodermal differentiation potential of human pluripotent stem cell lines. Scientific Reports.2016:DOI: 10.1038/srep37178. (*corresponding).   

Mathapati S, Siller R, Impellizzeri AR, Lycke M, Vegheim K, Almass R and Sullivan GJ*. Small molecule directed hepatocytes like cells differentiation of human pluripotent stem cells. Curr. Protoc. Stem Cell Biol.2016:38:1G.6.1-1G.6.18.doi: 10.1002/cpsc.13. (*corresponding).   

Xu M, Stattin E-L, Shaw G, Heinegård D, Sullivan G, Wilmut I, Colman A, Önnerfjord P, Khabut A, Aspberg A, Dockery P, Hardingham T, Murphy M, Barry F. Chondrocytes derived from mesenchymal stromal cells and induced pluripotent cells of patients with familial osteochondritis dissecans exhibit an ER stress response and defective matrix assembly. Stem Cells Transl. Med. 2016: 5:1171-1181.

Siller R, Greenhough S, Naumovska E and Sullivan GJ*.Small molecule driven hepatocyte differentiation of human pluripotent stem cells. Stem Cell Reports. 2015: 4:939-952. (*corresponding).   

Siller R, Greenhough S, Park IH and Sullivan GJ*. Modelling human disease with pluripotent stem cells. Current Gene Therapy. 2013: 13:99-110. (*corresponding).   

Dajani R, Koo SE, Sullivan GJ*, Park IH*. Investigation of Rett syndrome using pluripotent stem cells. J Cell Biochem2013: 114:2446-2453 (*co-corresponding). 

Bilican B, Serio A, Barmada SJ, Nishimura AL, Sullivan GJ,Carrasco M, Phatnani HP, Puddifoot CA, Story D, Fletcher J, Park IH, Friedman BA, Daley GQ, Wyllie DJ, Hardingham GE, Wilmut I, Finkbeiner S, Maniatis T, Shaw CE, Chandran S. (2013) Comment on "Drug screening for ALS using patient-specific induced pluripotent stem cells".  Sci Transl Med. 5(188):188le2.

Kim KY, Jung YW, Sullivan GJ, Chung L and Park IH. Cellular Reprogramming: a novel tool in investigating ASDs. Trends Mol Med 2012: 18:463-71.

Yamazaki T, Chen S, Yu Y, Yan B, Carrasco MA, Tapia JC, Zhai B, Das R, Lalancette-Hebert M, Sharma A, Chandran S, Sullivan G,Nishimura AL, Shaw CE, Gygi SP, Shneider NA, Maniatis T, and Reed R.FUS-SMN protein interactions link the motor neuron diseases ALS and SMA. Cell Rep. 2012: 25;2:799-806. F1000 recommended.

Bilican B, Serio A, Barmada SJ, Nishimura AL, Sullivan GJ,Carrasco M, Phatnani HP, Puddifoot CA, Story D, Fletcher J, Park IH, Friedman BA, Daley GQ, Wyllie DJ, Hardingham GE, Wilmut I, Finkbeiner S, Maniatis T, Shaw CE, Chandran S. Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability. Proc Natl Acad Sci USA.2012: 109:5803-8. F1000 recommended.

Zhou XL, Sullivan GJ,Sun P, and Park IH. Humanized murine model for HBV and HCV using human induced pluripotent stem cells. Archives of Pharmacal Research. 2012: 35:261-269.

Hysolli E, Zhou XL, Liu R, Kim JH, Adams B, Sullivan GJ, and Park IH. Role of Pluripotent Stem Cells in Regenerative Medicine. Regenerative Medicine, Stem Cells and the Liver. Book Chapter, March 15, (2012) by Science Publishers.

Wilmut I, Sullivan G and Chambers I.  The evolving biology of cell reprogramming. Philosophical Transactions of the Royal Society B. Philosophical Transactions of the Royal Society B.  2011: 366:2183-2197.

Wilmut I, Wongtawan T, Quigley M and Sullivan GJ.  Biomedical and social contributions to sustainability. Philosophical Transactions of the Royal Society A.2011: 369:1730-1747.

Ruzov A,  Tsenkina Y, Serio A, Dudnakova T, Fletcher J, Bai Y, Chebotareva T, Pells S, Hannoun Z, Sullivan GJ,Chandran S, Hay D, Bradley M, Wilmut I and De Sousa P.  Lineage specific distribution of high levels of genomic 5-hydroxymethylcytosine in mammalian development. Cell Research. 2011: 21:1332-42.

Sullivan GJ,Bai YM, Fletcher J and Wilmut I.Induced pluripotent stem cells: epigenetic memories and practical implications. Molecular Human Reproduction. 2010: 16:880–885.

Hannoun Z, Filippi C, Sullivan GJ,Hay DC and Iredale JP. Hepatic Endoderm Differentiation from Human Embryonic Stem Cells. Current Stem Cell Research &Therapy. 2010: 5:233-244.

SullivanGJ*,Hay DC, Park IH, Fletcher J, Hannoun Z, Payne CM, Dalgetty D, Black JR, Ross JA, Samuel K, Wang G, Daley GQ, Lee JH, Church GM, Forbes SJ, Iredale JP and Wilmut I.Generation of functional human hepatic endoderm from human induced pluripotent stem cells. Hepatology.2010: 51:329-335. (*corresponding). F1000 recommended. Editiorial Hepatology and Press coverage BBC.

Taylor J, Wilmut I, Sullivan GJ. What are the limits to cell plasticity? [Research Highlight] Cell Research.2010: 20:502-503.

 

Arne Klungland group

Laboratory for Genome repair and regulation

Institute of Medical Microbiology, Section for Molecular Biology, is localised at Oslo University Hospital, Rikshospitalet,  Gaustad, Oslo. Four different research groups are colocalised, concentrating on DNA-repair and epigenetic studies, brain development, microbiology and biocomputing. 

We have a very close collaboration with the Bjørås group which is also a part of the Stem Cell Centre, as well as  biocomputing collaborations with the Rognes group. For characterization of knockout mice we collaborate with the Falnes (University of Oslo) and Krokan (University in Trondheim) groups. We also collaborate with excellent research groups in Germany, France, China, Holland, UK and USA. 

Our aim is to elucidate new mechanisms of demethylation and hydroxylation required for for repair and regulation of the mammalian (epi)genome and to address (epi)genome instabilities associated with diseases such as cancer. Our current models also include genes affecting post translational modifications in RNA and proteins. 

Currently we have MSc ("hovedfag"), PhD students and post docs from The Agricultural University, University of Oslo, University of Trondheim ("Siv. Ing."), Austria, Sweden, The Phillipines, Germany and USA. 

Selected publications (2006-2012):

Robertson AR, Dahl JA, Ougland R and Klungland A (2012) 5-hydroxymethylcytosine DNA pull down using JBP1-coated magnetic beads. Nature protocols, 7:340-50

Robertson A, Dahl JA, Vågbø C, Tripathi P, Krokan H and Klungland A (2011) A novel method for the efficient and selective identification of 5-hydroxymethylcytosine in genomic DNA. Nucleic Acids Res 39:e55*

     *The method described is patented and released by ZYMO research, USA.

van den Born E*1, Vågbø CB*1, Songe-Møller L*1, Leihne V, Lien GF, Krokan HE, Kirpekar F, Klungland A*2 and Falnes PØ*2 (2011) ALKBH8 mediated hydroxylation of a novel diastereomeric pair of wobble nucleosides in tRNA. Nature Commun 2, 172 *1Contributed equally *2 Corresponding

Haj-Yasein NN, Vindedal GF, Eilert-Olsen M, Gundersen GA, Skare Ø, Laake P, Klungland A, Thorén AE, Burkhardt JM, Ottersen OP and Nagelhus EA (2011) Glial-conditional deletion of aquaporin-4 (Aqp4) reduces blood-brain water uptake and confers barrier function on perivascular astrocyte endfeet. Proc Natl Acad Sci USA 108:17815-20

Thrane AS*, Rappold PM*, Fujita T, Torres A, Bekar LK, Takano T, Peng W, Wang F, Thrane VR, Enger R, Haj-Yasein NN, Skare Ø, Holen T, Klungland A, Ottersen OP, Nedergaard M and Nagelhus EA (2011) Critical role of aquaporin-4 (AQP4) in astrocytic Ca2+ signaling events elicited by cerebral edema. Proc Natl Acad Sci USA 108:846-51 *Contributed equally

Strømme S, Dobrenis K, Sillitoe R, Gullinello M, Ali N, Davidson C, Micsenyi MC, Stephney G, Ellevog L, Klungland A and Walkley SU (2011) Sodium/Hydrogen exchanger related mental retardation syndrome: evidence for endosomal-lysosomal dysfunction in Slc9a6 targeted mice. Brain

Møllersen L*, Rowe AD*, Larsen E, Rognes T and Klungland A (2010) Two modes of somatic CAG repeat expansions in Huntington disease transgenic mice. PLoS Genet 9;6 *Corresponding

Songe-Møller L*1, van den Born E*1, Leihne V*1, Vågbø CB*1, Kristoffersen T, Krokan HE, Kirpekar F, Falnes PØ*1,2 and Klungland A*1,2  (2010) Mammalian ALKBH8 possesses tRNA methyltransferase activity required for the biogenesis of multiple wobble uridine modifications implicated in translational decoding. Mol Cell Biol 30:1814-27 *1Contributed equally *2Corresponding

Lauritzen KH, Moldestad O, Eide L, Carlsen H, Nesse G, Storm JF, Mansuy IM, Bergersen LH* and Klungland A* (2010) Mitochondrial DNA toxicity in forebrain neurons causes apoptosis, neurodegeneration, and impaired behavior. Mol Cell Biol 30:1357-67 *Corresponding

Saxowsky T, Meadows K, Klungland A and Doetsch P (2008) 8-Oxoguanine-mediated transcriptional mutagenesis causes Ras activation in mammalian cells. Proc Natl Acad Sci USA 105:18877-82

Larsen E*, Kleppa L*, Meza TJ, Meza-Zepeda LA, Rada C, Castellanos CG, Lien GF, Nesse GJ, Neuberger MS, Lærdahl JG, Doughty RW and Klungland A (2008) Early onset lymphoma and extensive embryonic apoptosis in two domain-specific Fen1 mice mutants. Cancer Res 68:4571-9 *Contributed equally

Ringvoll J, Nabong MP, Nordstrand LM, Meira L, Pang B, Dedon P, Bjelland S, Samson LD, Falnes PØ and Klungland A (2008) AlkB homolog 2 (ABH2) is the principal mammalian dioxygenase for repair of ethenoadenine lesions in DNA. Cancer Res 68:4142-9

Kovtun IV, Liu Y, Bjørås M, Klungland A, Wilson SH and McMurray CT (2007) OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells. Nature 447:447-52

Leiros I*, Nabong MP*, Grosvik K, Ringvoll J, Haugland GT, Uldal L, Reite K, Olsbu IK, Knaevelsrud I, Moe E, Andersen OA, Birkeland NK, Ruoff P, Klungland A and Bjelland S (2007) Structural basis for enzymatic excision of N1-methyladenine and N3-methylcytosine from DNA. EMBO J 26:2206-17 *Contributed equally 

Ringvoll J, Nordstrand LM, Vågbø CB, Talstad V, Reite K, Aas PA, Lauritzen KH, Liabakk NB, Bjørk A, Doughty RW, Falnes PØ, Krokan HE, Klungland A (2006) Repair deficient mice reveal mABH2 as the primary oxidative demethylase for repairing 1meA and 3meC lesions in DNA. EMBO J 25:2189-98

Magnar Bjørås Group

Activities

DNA repair involves many distinct repair pathways, but the base excision repair (BER) pathway is postulated as the major pathway for removal of endogenously induced DNA damage, such as that arising from intracellular reactive oxygen species (ROS). The BER pathway has been the focus of our research for more than two decades, and we have identified several proteins involved in the pathway. Like other somatic cells and differentiated cells, the stem cells are equipped with DNA repair proteins that secure integrity of cellular DNA. DNA repair is especially important for the stem cell population, since mutations may limit their pluripotency. The aim of the stem cell research in the Bjørås laboratory is to explore the impact of BER for neuronal progenitor proliferation and differentiation, in which we are characterizing numerous BER knock-out mouse models.

 

Selected publications

Aukrust, P., Luna, L., Ueland, T., Johansen, R., Muller, F., Frøland, S., Seeberg, E., and Bjørås, M.
Enhanced oxidative DNA damage and decreased DNA glycosylase activity for removal of oxidative base lesions in CD4+ T cells during human immunodeficiency virus (HIV) infection - possibly pathogenic role of enhanced oxidative stress HIV related immunodeficiency.
Blood 105, 4730-5, (2005). 

Hildrestrand, Gunn; Diep, Dzung; Kunke, David; Backman, Mattias; Bolstad, Nils;Bjørås, Magnar; Krauss, Stefan; Luna, Luisa
The capacity to remove 8-oxoG is enhanced in neural stem/progenitor cells and decreases with age and upon cell differentiation.
DNA repair , 723-32, 6 (2007)

Kovtun, IV., Liang, Y., Bjørås, M., Klungland, A., Wilson, W. and McMurray, CT.
OGG1 initiates age-dependent somatic CAG expansion during normal base excision repair of oxidized bases in vitro and in vivo.
Nature, 447-52, 447 (2007)

Rolseth, V., Runden-Pran, E., Neurauter, C, Yndestad, A., Luna, L., Ottersen, OP., Bjørås, M
Base excision repair activities in organotypic hippocampal slice cultures exposed to oxygen and glucose deprivation.
DNA repair, 7, 869-78 (2008)

Rolseth, V., Runden-Pran, E.,  Luna, L., Bjørås, M., Ottersen, OP.
Widespread and differential distribution of DNA glycosylases removing oxidative DNA lesions in the human and rodent brain.
DNA repair . 7, 1578-88 (2008).

Dalhus, B., Arvy, A., Rosnes, I., Alseth, I., Cao, W., Olsen, ØE., Tainer, J.,Bjørås, M.
Structural basis of repair of deaminated adenine in  DNA by EndonucleaseV.
Nature Struct. Mol. Biol., 16, 138-43 (2009)

Gunn A. Hildrestrand, Shivali Duggal, Magnar Bjørås, Luisa Luna and Jan E. Brinchmann
Modulation of DNA glycosylase activities in mesenchymal stem cells.
Exp. Cell Res. 315, 2558-67 (2009)

Hildrestrand, G., Neurauter C., Diep, D., Castellanos, C., Krauss, S., Bjørås, M., Luna, L.
Expression patterns of Neil3 during embryonic brain development and neoplasia.
BMC Neurosci, 10, 45 (2009)

Bjørn Dalhus, Jon K. Laerdahl, Paul H., Backe, Magnar Bjørås.
DNA base repair - recognition and initiation of catalysis.
FEMS Microbiol. Rev, 33, 1044-78 (2009)

Pauline Isakson, Magnar Bjørås, Stig Ove Bøe and Anne Simonsen
Autophagy contributes to therapy-induced degradation of the PML/RARA oncoprotein
Blood. 116, 2324-31, (2010)

Wei Wang, Pia Osenbroch, Ragnhild Skinnes, Ying Esbensen, Magnar Bjørås and Lars Eide
The OGG1  DNA glycosylase is essential for proper mitochondrial maturation during differentiation of neural stem cells.
Stem Cells 28, 2195-204 (2010)

Wei Wang, Ying Esbensen, David Kunke, Rajikala Suganthan, Magnar Bjørås, Lars Eide.
Mitochondrial DNA Damage level determines Neural Stem Cell differentiation fate.
J. of Neuroscience 2011 Jun 29;31(26):9746-51

Yngve Sejersted, Gunn Annette Hildrestrand,David Kunke,Veslemøy Rolseth, Silje Zandstra Krokeide, Christine Gran Neurauter, Rajikala Suganthan, Monica Atneosen-Aasegg, Aaron M. Fleming, Ola Didrik Saugstad,Cynthia J. Burrows, Luisa Luna and Magnar Bjørås
Endonuclease III like (Neil3) DNA glycosylase.
PNAS. 2011 Nov 15;108(46):18802-7.

Møllersen L, Rowe AD, Illuzzi JL, Hildrestrand GA, Gerhold KJ, Tveterås L, Bjølgerud A, Wilson DM 3rd, Bjørås M, Klungland A.
Neil1 is a genetic modifier of somatic and germline CAG trinucleotide repeat instability in R6/1 mice.
Hum Mol Genet. 2012. 21:4939-47.

Jalland CMO, Benestad SL, Ersdal C, Scheffler K, Suganthan R, Nakabeppu Y, Eide L, Bjørås M, Tranulis M.
Accelerated clinical course of prion disease in mice compromised in repair of oxidative DNA damage.
Free Radic Biol Med. 2014.Mar 1;68C:1-7.

Regnell CE, Hildrestrand GA, Sejersted Y, Medin T, Moldestad O, Rolseth V, Zandstra SK, Suganthan R, Luna L, Bjørås M*, Bergersen LH*. Hippocampal adult neurogenesis is maintained by Neil3-dependent repair of oxidative DNA lesions in neural progenitor cells.
Cell Reports. 2012, 2:503-10. *Corresponding authors and contributed equally.

Yang M, Lin X, Rowe A, Rognes T, EideL, Bjørås M.
Transcriptome analysis of human OXR1 depleted cells reveals its role in regulating the p53 signaling pathway.
Sci Rep, 2015 Nov 30;5:17409. doi: 10.1038/srep17409

Yang M, Luna L, Sørbø JG, Alseth I, Johansen RF, Backe PH, Danbolt NC, Eide L, Bjørås M.
Human OXR1 maintains mitochondrial DNA integrity and ROS balance by regulating antioxidant pathways involving p21. 
Free Radic Biol Med. 2014;77:41-8.

Bjørge MD, Hildrestrand GA, Scheffler K, Suganthan R, Rolseth V, Kuœnierczyk A, Rowe AD, Vågbø CB, Vetlesen S, Eide L, Slupphaug G, Nakabeppu Y, Bredy TW, Klungland A and Bjørås M.
Synergistic actions of Ogg1 and Mutyh DNA glycosylases modulate anxiety-like behavior in mice.
Cell Reports. 2015. 13(12):2671-8. 

Skarpengland T Holm S, Scheffler K, Gregersen I, Dahl TB, Suganthan R, Segers FM, Østlie I, Otten JJ, Luna L, Ketelhuth DF, Lundberg AM, Neurauter CG, Hildrestrand G, Skjelland M, Bjørndal B, Svardal AM, Iversen PO, Hedin U, Nygård S, Olstad OK, Krohg-Sørensen K, Slupphaug G, Eide L, Kuœnierczyk A, Folkersen L, Ueland T, Berge RK, Hansson GK, Biessen EA, Halvorsen B#, Bjørås M#, Aukrust P#.
Neil3 dependent base excision repair regulates lipid metabolism and prevents atherosclerosis.
Sci Rep 2016. 22;6:28337

Palibrk V, Suganthan R, Scheffler K, Wang W, Bjørås M# and Bøe SO.
PML# regulates neuroprotective innate immunity and neuroblast commitment in a hypoxia ischemic encephalopathy model.
Cell Death and Disease. 2016. 7(7):e2320 .

Dahl JA, Jung I, Aanes H, Greggains GD, Mana A, Lerdrup M, Li G, Kuan S, Li B, Lee AY, Preissl S, JermstadI, Haugen MH, Suganthan R, Bjørås M, Hansen K, Dalen KT, Fedorcsak P, Ren B, Klungland A.
Broad histone H3K4me3 domains in mouse oocytes modulate maternal to zygotic transition.
Nature, Sep 14;537(7621):548-55

Jalland C, Scheffler K, Benestad S, Moldal T, Ersdal C, Gunnes G, Suganthan R, Bjørås M,  Tranulis M.
Neil3 induced neurogenesis protects against prion disease during the clinical phase.
Sci Reports. In press

Rydning SL, Backe PH, Sousa MML, Iqbal Z, Øye AM, Sheng Y, Yang M, Lin X, Slupphaug G, Nordenmark TH, Vigeland MD, Bjørås M, Tallaksen CH and Selmer KK.
Novel UCHL1-mutations reveal new insights into ubiquitin processing.
Human Molecular Genetics, 2016Dec 22. pii: ddw391. doi: 10.1093/hmg/ddw391

Olsen MB, Hildrestrand GA, Scheffler K, Vinge LE, Alfsnes K, Palibrk V, Neurauter CG, Luna L, Johansen J, Øgaard JD, Ohma IK, Slupphaug G, Kuœnierczyk A, Fiane AE, Brorson SH, Zhang L, Gullestad L, Louch W, Iversen PO, Østlie I, Klungland A, Christensenc G, Sjaastad I,  Sætrom P, Yndestad A, Aukrust P#, Bjørås M# and Finsen A#.
NEIL3-dependent regulation of cardiac fibroblast proliferation prevents myocardial rupture. 
Cell Reports, 2017. 18(1):82-92.

Jan Øivind Moskaug group

IN MEMORIUM

Jan Øivind Moskaug
1957-2018

It is with great sadness that we inform all of our colleagues, friends and associates that Jan Øivind Moskaug passed away on Friday, May 11, 2018, after battling cancer for a year.

Jan Øivind was a group leader at the Stem Cell Center from its inception in 2009. He was actively pursuing the role of mesenchymal stem cells in modulating inflammation in animal models and their utilization for tissue reconstruction in clinical trials. He was a devoted teacher, and a clear voice for responsible and ethical practice in scientific research. He will be sorely missed.

 

About

Adipose stem cells are interesting both in relation to human pandemic obesity and as dispensible source of multipotent mesenchymal stem cells in regenerative medicine. Our laboratory is interested in elucidating functional aspects of adipose stem cells in mice, with particular emphasis on their function after tissue implantation. Our research group consists of 1 post. doc and 1 Ph.D. student dedicated to understand how adult stem cells may influence inflammatory processes in mice. We combine animal disease models in transgenic mice with state-of-art in vivo imaging of labelled stem cells to address these issues.

Challenges

The long-term goal of our work is to understand how mesenchymal stem cells might influence disease progression when transplanted into dysfunctional tissues. A secondary goal is to characterize conditions of nutritional relevance that influence differentiation potential, first in vitro and secondly in vivo. To reach this goal, we are (i) establishing protocols for multimodal optical imaging of stem cells in inflammatory animal models, and (ii) systematically varying adipose stem cells culture condition with respect to critical components to assess consequences for their immun modulatory activies.  

Projects

  • Development of protocols for adipose stem cell imaging in vivo.
    This project includes generation of luminescent and fluorescent reporters, either constitutively or differentially expressed. Genetic labelling of cells is complemented with labeling with magnetic and fluorescent beads compatible with MR imaging. Optical and magnetic imaging modalities is compared regarding signal intensity, S/N ratios, tissue compatibility, resolution and duration.
     
  • Immuno modulatory activities of adipose stem cells.
    This project investigates factors released by adipose stem cells that modulate NF-kB responses in macrophages with possible consequences for the immuno regulatory functions of mesenchynal stem cells in vivo.
     
  • Nutritional factors influencing adipose stem cell diffenetiation and function.
    Adipocyte differentiation is studied in vitro as a function of carbohydrate and fatty acid availablility.
     

Collaborations

  • Prof. Helga Refsum and prof. Hilde Nebb, Institute of Basic Medical Sciences, Department of  Nutrition, Univeristy of Oslo, Norway: Cystein metabolism and adipose stem cell differentiation.  
  • Prof. Philippe Collas, Institute of Basic Medical Sciences, Department of  Nutrition, Univeristy of Oslo, Norway: Epigenetic profiling of mouse adipose stem cells.
  • Prof. Joel Glover, Institute of Basic Medical Sciences, Department of  Physiology, Univeristy of Oslo, Norway: Imaging modalities for stem cell tracking and localization.

Selected publications

Research groups

The Center stands at 11 core member groups of which 5 (Brinchmann, Collas, Glover, Moskaug, Sullivan) are physically co-localized at Domus Medica, and 3 (Langmoen, Klungland, Bjørås) in close proximity (5 min walking distance) at OUS-Rikshospitalet. The other 3 core member groups are physically distant (Moe at OUS-Ullevål, Staerk at Forskningsparken and Kvalheim at OUS-Radiumhospital). Nevertheless, these group leaders and their groups participate regularly and actively in group leader meetings and other Center activities including courses, seminars and social events.

From 2016 the group has included 3 recruitment members:

Ragnhild Eskeland (PhD, Principal Investigator, Department of Biosciences, University of Oslo)
Adam Filipzcyk (Researcher, Department of Microbiology, OUS-Rikshospitalet)
Hanne Scholz (MSc, PhD, Head of Cell Transplantation Research and the Islet Isolation Facility Institute for Surgical Reaserch, OUS Rikshospitalet)

 

Overview of groups

Magnar Bjørås group

Jan E. Brinchmann group

Philippe Collas group

Joel Glover group

Arne Klungland group

Iver Langmoen group

Morten C. Moe group

Jan Øivind Moskaug group

Judith Staerk group

Gareth Sullivan group

Morten C. Moe group Center for Eye Research

Center for Eye Research, University of Oslo, is located at Dep.of Ophthalmology at Oslo University Hospital.

Professor Bjørn Nicolaissen is head of the Center. We have wide experience in tissue- and cell culture procedures, as well as a range of analytical procedures including ultrastructural- (electron microscopy), immunohistochemical-, and molecular biological-  analyses. Presently, our clinic has the only Program in Scandinavia, for transplantation of ex vivo generated ocular tissue for anterior segment surgery, including autologous transplantation of limbal stem cells performed by Professor Liv Drolsum and conjunctival tissue performed by consultant oculoplastic surgeon Dag Krohn-Hansen.

Associate Professor Morten C. Moe and Senior Scientist Aboulghassem Shahdadfar is heading the translational research projects at the Center, where isolation and characterization of stem cells from the adult human eye is one of the main strategic research focuses. There are currently 7 PhD students at the Center.

 Main collaboration partners:

  • Vilhelm Magnus Laboratory/ Inst. For Surgical Research, OUS
  • Dep. of Pathology, OUS
  • Dep. of Nutrition, UiO
  • Inst. for Oral biology, UiO
  • Centre for Molecular Biology and Neuroscience, UiO
  • Ofthalmologica del Mediterraneo, Research Unit, Valencia, Spain.
  • Medical and HealthScience Center, University of Debrecen, Hungary
  • VA Western NY Healthcare System,Buffalo, USA
  • OcuSuRe Reserach Alliance

 Selected publications Morten C. Moe

  • Westerlund U, Moe MC, Varghese M, Berg-Johnsen J, Ohlsson M, Langmoen IA, Svensson S.. Stem Cells Harvested from the Adult Human Brain Develop into Functional Neurons. Exp Cell Res. 2003 Oct 1;289(2):378-83.
  • Moe MC, Westerlund U, Varghese M, Berg-Johnsen J, Langmoen IA, Svensson M. Development of neuronal networks from single stem cells harvested from the adult human brain. NEUROSURGERY. 2005 Jun;56(6): 1182-8.
  • Moe MC, Varghese M, Westerlund U, Ramm-Pettersen J, Danilov AI, Brundin L, Svensson M, Berg-Johnsen J and Langmoen IA. Multipotent progenitor cells from the adult human brain: Neurophysiological differentiation to mature neurons. BRAIN 2005 Sep;128(Pt 9):2189-99.
  • Covacu R, Danilov AI, Rasmussen BS, Hallen K, Moe MC, Lobell A, Johansson CB, Svensson MA, Olsson T, Brundin L. Nitric Oxide Exposure Diverts Neural Stem Cell Fate from Neurogenesis towards Astrogliogenesis. Stem Cells. 2006 Dec; 24(12):2792-800.
  • Varghese M, Olstorn H , Sandberg C, Vik-Mo EO, Noordhuis P, Nister M, Berg-Johnsen J , Moe MC, Langmoen IA. A Comparison between Stem Cells from the Adult Human Brain and Brain Tumors. NEUROSURGERY, Neurosurgery. 2008 Dec; 63(6):1022-33.
  • Moe MC, Froen RC, Sandberg C, Vik-Mo E, Olstorn H, Langmoen IA, Nicolaissen B. A comparison of epithelial and neural properties in progenitor cells derived from the adult human ciliary body and brain. Experimental Eye Research, 2009 Jan;88(1):30-8.
  • Fodor M, Petrovski G, Moe MC, Németh G, Dinya Z, Tormai I, Bíró Z, Újvári T, Berta A and Facskó A. Spectrographic study of explanted opacified and originally packed hydrophilic acrylic intraocular lenses. Acta Ophthalmologica, 2010 May 19.
  • Petrovski G, Berényi E, Moe MC, Vajas A, Fésüs L, Facsko A and Berta A. Clearance of dying ARPE-19 cells by professional and non-professional phagocytes in vitro - implications for age-related macular degeneration (AMD). Acta Ophthalmol. 2010 Nov 23.
  • Frøen R, Johnsen EO, Nicolaissen B, Berenyi E, Berta A, Petrovski G and Moe MC. Isolation of neuroepithelial progenitor cells from human peripheral iridectomies. Submitted.

Philippe Collas group

 

Chromatin and nuclear architecture in stem cells

The CollasLab investigates principles of 3-dimensional genome architecture which pattern lineage-specific stem cell differentiation in health and disease contexts.
See also www.collaslab.org.

 

Research goal

The 3D layout of chromatin plays important roles in the establishment of gene expression programs governing cell fate decisions.We are addressing three main questions:

  • How is 3D genome conformation regulated during fat stem cell differentiation?
  • How do laminopathy-causing lamin mutations affect chromatin conformation?
  • How do histone H3 variants contribute to chromatin homeostasis in normal and cancer cells?

Our work combines cell biological, genomics and genome structure modeling approaches using patient material and engineered stem cells.

 

The lab’s research history in brief

  • disassembly and reformation of the nuclear envelope (Steen 2000 J Cell Biol; Steen 2001 J Cell Biol; Martins 2003 J Cell Biol)
  • cell and nuclear reprogramming (Håkelien 2002 Nature Biotech; Taranger 2005 Mol Biol Cell; Freberg 2007 Mol Biol Cell)
  • chromatin immunoprecipitation (ChIP) assays for small cell numbers (Dahl 2008 Nature Protoc; 2009 Genome Biol)
  • epigenetic patterning of developmental gene expression (Lindeman 2011 Dev Cell; Andersen 2012 Genome Biol) and of adipose stem cell differentiation (Boquest 2007 Stem Cells; Sørensen 2010 Mol Biol Cell; Shah 2014 BMC Genomics; Rønningen 2015 BBRC)
  • nuclear lamin - chromatin interactions during adipogenic differentiation (Lund 2013 Genome Res; Lund 2014 Nucl Acids Res; Oldenburg 2014 Hum Mol Genet; Rønningen 2015 Genome Res)
  • deposition of histone H3 variants into chromatin (Delbarre 2010 Mol Biol Cell; Delbarre 2013 Genome Res; Ivanauskiene 2014 Genome Res; Delbarre 2017 Genome Res)
  • 3D genome modeling (Paulsen 2015 PloS Comput Biol; Sekelja 2016 Genome Biol; Paulsen 2017 Genome Biol)

 

Projects:

 

3D organization of the stem cell genome

3D genome organization of the genome influences cell- and time-specific blueprints of gene expression. Some aspects of 3D genome conformation vary between cell types, suggesting developmental regulation. 3D genome conformation entails interactions between chromosomes, forming interactions hubs called topologically-associating domains (TADs). At the nuclear periphery, chromosomes interact with the nuclear lamina through lamin-associated domains (LADs). These interactions are dynamic during differentiation. We are investigating links between cellular metabolism and changes in spatial genome conformation during differentiation of adipose stem cells in normal and pathological conditions.

Ongoing research:

  • Computational methods for 3D and 4D modeling of genome architecture
  • Functional relationships between 3D chromatin folding, nuclear envelope-chromatin interactions, epigenetic states and lineage-specific differentiation capacity

 

Nuclear lamina, genome organization & adipose stem cell function

The nuclear envelope regulates gene expression by interacting with chromatin. It consists of a double nuclear membrane, nuclear pores and the nuclear lamina, a meshwork of A-type lamins (LMNA, LMNC) and B-type lamins (LMNB1, LMNB2). Mutations in LMNA cause laminopathies, which include progeria, muscle dystrophies and partial lipodystrophies. Familial partial lipodystrophy of Dunnigan type (FPLD2) mainly affects adipose tissue and leads to severe metabolic disorders. We use patient cells, patient-derived iPS cells and engineered adipose stem cells to address the impact of lipodystrophic LMNA mutations on differentiation of adipose stem cells (ASCs), formation and composition of LADs and 3D genome conformation.

Ongoing research:

  • Identification of determinants of nuclear envelope-chromatin interactions during lineage-specific differentiation and in laminopathy contexts
  • Bioinformatics development

 

Histone variants and chromatin homeostasis

A class of pediatric gliomas (diffuse intrinsic pontine gliomas, DIPGs), is driven by mutations in the H3F3A gene encoding histone variant H3.3. The most prominent DIPG driver H3.3 mutation is H3.3K27M, which results in global reduction of H3K27me3. Other H3.3 mutations include H3.3G34R, which affects other nearby H3 modifications.

Ongoing research:

  • Mechanisms of deposition of histone H3 variants into chromatin
  • Role of H3.3 on  chromatin homeostasis
  • Impact of H3.3 mutations on chromatin and nuclear architecture in glioblastomas

 

Key collaborations

  • Louis Casteilla, StromaLab, University of Toulouse, France (adipose tissue metabolism)
  • Jacques Grill, Institut Gustave Roussy, Villejuif, France (H3.3 mutations and pediatric glioblastoma)
  • Anna Kostareva, Almazov Research Center, St. Petersburg, Russia (mesenchymal stem cells)
  • Stefan Pfister, DKFZ, Heidelberg, Germany (pediatric glioblastoma)
  • Corinne Vigouroux, Hôpital Saint Antoine, INSERM, Paris, France (lipodystrophies)
  • Lee Wong, Monash University, Clayton, Australia (heterochromatin)
  • David Tremethick, John Curtis School of Medical Research, Australian National University, Canberra, Australia (genome conformation)

  

Some recent publications

Delbarre, E, Ivanauskiene K, Spirkoski J, Shah A, Vekterud K, Moskaug JØ, Bøe SO, Wong L, Küntziger T, Collas P. 2017. PML protein organizes heterochromatin domains where it regulates histone H3.3 deposition by ATRX/DAXX. Genome Res. In press.

Paulsen J, Sekelja M, Oldenburg AR, Barateau A, Briand N, Delbarre E, Shah, A, Sørensen AL, Vigouroux C, Buendia B, Collas P. 2017. Chrom3D: three-dimensional genome modeling from Hi-C and nuclear lamin-genome contacts. Genome Biol. 18, 21-29.

Sekelja M., Paulsen J., Collas P. 2016. 4D nucleomes in single cells: what can computational modeling reveal about spatial chromatin conformation? Genome Biol 17, 54

Rønningen T., Shah A, Oldenburg AR, Vekterud K, Delbarre E, Moskaug JØ, Collas P. 2015. Prepatterning of differentiation-driven nuclear lamin A/C-associated chromatin domains by GlcNAcylated histone H2B. Genome Res 25, 1825-1835.

Ivanauskiené K., Delbarre E., McGhie J.D., Küntziger T., Wong L.H., Collas P. 2014. The PML-associated protein DEK regulates the balance of H3.3 loading on chromatin and is important for for telomere integrity. Genome Res. 24, 1584-1594