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Researchers
  • Dr.  Michael Berger
Dr Michael Berger
 
Research Summary 
Topic: Genetic and biochemical dissection of quiescence in immune cells.
 
The immune system maintains a vast repertoire of B and T-cells waiting to respond to microbial invasion. These cells are kept in a quiescent state, characterized by arrest in G0 and a decrease in cell size and metabolic activity, until they are activated by antigen engagement and co-stimulation to acquire their effector functions. During the past two decades, numerous types of signalling and changes in gene expression leading to lymphocyte activation, expansion, and acquisition of effector functions have been described. However, the nature and molecular enforcement of quiescence is far from being elucidated. In fact not long ago quiescence was considered equivalent to “absence of activation”, namely a default state of the cell. Recently our discovery of a chemically induced mutation, elektra, enabled us to provide a dramatic illustration of what happens when quiescence fails. Mice homozygous for this mutation showed an abnormally high frequency of lymphocytes in a semi-activated state and suffered from immunodeficiency. We ascribed the elektra phenotype to a mutation in Slfn2, a gene of previously unknown function, and concluded that SLFN2 plays an essential role in immune defense, where it operates to maintain quiescence in specific populations of immune cells. Our results were somewhat surprising; we would expect that the elimination of a regulator of quiescence would lead to hyperactive immune responses and even autoimmunity. However, our finding that the Slfn2 mutation disrupts quiescence, and that this in turn leads to immunodeficiency, demonstrated that the exact opposite could happen. These results suggest that quiescence programming has a broader role in immunity than was previously recognized, and that although it is an active process that enforces passiveness, quiescence itself is by no means passive. Therefore, the factors regulating the quiescence process may have the potential to be exploited for therapeutic purposes in immune diseases, either by enhancing specific anti-pathogen and anti-tumor immune responses or by suppressing overactive, self-directed responses observed in autoimmune diseases, allergy, graft-versus-host disease, and allogeneic transplantation. Fulfillment of this potential is not yet within reach because lymphocyte quiescence is still poorly understood and many issues remain to be addressed. For example: what signals are responsible for maintaining quiescence?  And what are the factors that sense those signals, translating them into activation of quiescence-maintaining transcription factors?
 
The aim of my research is to clarify these crucial questions. We are employing traditional molecular approaches in combination with unbiased functional forward genetic screening to provide comprehensive and integrative insights into the factors and mechanisms that establish and maintain lymphocyte quiescence.
 
 
 
 
Research Projects 
       ·        Elucidate key molecular processes maintaining quiescence in immune cells.
 
       ·        Immune memory: uncover the roles of quiescence maintaining genes in the differentiation of memory T-cells.
      
       ·        Cancer research: the role of the quiescence inducer, SLFN2, in T-ALL (T-cell acute lymphoblastic leukemia) development.
 
 
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Lab Members 
Michael Berger, Head of the lab
 
Ibrahim Omar, PhD. Student
 
Mirit Musseri, Msc. student
 
Aviya Goldshtein, Msc. Student
 
Eleanor Rachi, Lab technician
 
Beni Shlezinger, project student 
 
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Curriculum Vitae 
Education
 
1999 ‒ 2005
PhD student, Faculty of Medicine, The Hebrew University of Jerusalem, Israel. (Prof. Ygal Haupt’s laboratory; Dissertation: “Regulation of the p53 protein: A role for the poly-proline rich region.” (PhD awarded June 2006).
 
1998 ‒ 1999
MSc student, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel. (Prof. Ygal Haupt’s laboratory.) Moved to a “direct track” PhD program.
 
1993 ‒ 1996
BSc student, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Israel. (Degree awarded magna cum laude.)
 
Experience
 
July 2011
Senior Lecturer, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Israel.
     • Genetic and biochemical dissection of quiescence in immune cells.
     • Role of quiescent regulatory networks in the differentiation and function of inflammatory monocytes (IMs). 
     • Establishment and maintenance of T-cell memory.
     • Involvement of the Schlafen gene family in development of chronic myelogenous leukemia (CML).
 
2010 ‒ 2011
Senior Research Associate, laboratory of Prof. Bruce Beutler, Department of Genetics, The Scripps Research Institute (TSRI), CA, USA.
     • Genetic and biochemical analysis of immune quiescence enforced by SLFN2.
          i. Detailed molecular study of the SLFN2 pathway.
          ii. Design of a genetic screen to elucidate key molecular processes regulated by SLFN2.
 
2005 ‒ 2010
Postdoctoral Fellow, laboratory of Prof. Bruce Beutler, Department of Genetics, TSRI, CA, USA.
     • Analysis of the host defense response to viral infection.
          i. Ascribed the elektra phenotype to a mutation in the Slfn2 gene.
          ii. Demonstrated that a Slfn2 mutation causes lymphoid and myeloid immunodeficiency due to loss of immune cell quiescence.
     • Toll-like receptor (TLR) signalling pathway.
          i. Discovered key molecules involved in the TLR signalling pathway.
          ii. Found new TLR agonists (in collaboration with Prof. Dale Boger, Department of Chemistry, TSRI).
 
2004 ‒ 2005
FACS Operator, The Core Research Facility, Hadassah Medical School, The Hebrew University of Jerusalem, Israel.
     • Allocated tasks included
          i. Providing consulting services and helping in experiment design. 
          ii. Performing flow cytometric data analysis.
 
1999 ‒ 2005
Ph.D. Student, laboratory of Prof. Ygal Haupt, The Lautenberg Center for General and Tumor Immunology, Hadassah Medical School, The Hebrew University of Jerusalem, Israel.
     • Carried out analysis of the p53-Mdm2 feedback loop.
          i. Showed that mutations in proline 82 of p53 uncouple its activation by Pin1 and Chk2 in response to DNA damage.
          ii. Ascribed a role for the poly-proline domain of p53 in its regulation by Mdm2.
          iii. Helped to uncover the role of Ser20 of human p53 in the negative regulation of p53 by Mdm2.
 
1999 ‒ 2004
Teaching Assistant, Department of Immunology, Hadassah Medical School, The Hebrew University of Jerusalem, Israel. 
     • Advanced lab course in immunology for PhD students.
          i. Taught flow cytometric techniques including data analysis.
          ii. Coached FACS machine operation: software and hardware.
 
1998 ‒ 1999
Teaching Assistant, Hadassah Medical School, The Hebrew University of Jerusalem, Israel. Lab course in microbiology for pharmacy students.
     • Taught basic techniques in microbiology.
 
1994 ‒ 1996
Research Assistant, laboratory of Prof. Daniel Michaelson, Department of Neurobiology, Tel Aviv University, Israel.
     • Analysis of the role of apolipoprotein E4 in Alzheimer’s disease: 
          i. Purified apolipoprotein E (ApoE) from neuronal cultured cells using fast protein liquid chromatography (FPLC).
          ii. Developed an ELISA protocol to measure levels of ApoE.
          iii. Maintained mouse colony.
 
Awards and Honors
 
2005 ‒ 2007
European Molecular Biology Organization (EMBO) long-term fellowship.
 
2003 
Award for Outstanding Excellency in Teaching, Hadassah Medical School, The Hebrew University of Jerusalem, Israel.
 
2002 ‒ 2004 
The Rector’s Ph.D. Scholarship for distinction, The Hebrew University of Jerusalem.
 
2001
Awarded by Keren Kayemet ‒ Jewish National Fund, from the Arthur and Ludmila Zucker Memorial Fund for Cancer Research.
 
2001
Excellency in Teaching Award, Hadassah Medical School, The Hebrew University of Jerusalem, Israel.
 
2000
Travel grant from NIH.
 
Presentations at scientific meetings
 
A Slfn2 mutation causes lymphoid and myeloid immunodeficiency due to loss of immune cell quiescence. EMBO US Fellows Meeting, La Jolla, CA, USA, November 2010. Invited speaker.
 
A Slfn2 mutation causes lymphoid and myeloid immunodeficiency due to loss of immune cell quiescence. La Jolla Immunology Conference, Salk Institute, La Jolla, CA, USA, October 2010. Selected talk (“Best Talk of the Meeting” award).
 
A Slfn2 mutation causes lymphoid and myeloid immunodeficiency due to loss of immune cell quiescence. T-cell Memory Workshop, Bethesda, MD, USA, September 2010. Invited speaker.
 
Elektra: a mutation impairing lymphoid development and resistance to MCMV infection EMBO US Fellows Meeting, Boston, MA, USA, November 2008. Invited speaker.
 
Analysis of the MCMV resistome by ENU mutagenesis- The elektra mutant. EMBO Fellows Meeting, Heidelberg, Germany, June 2008. Invited speaker.
 
Genetic analysis of the Toll-like receptor signalling pathways. 20th International Mammalian Genome Conference, Charleston, SC, USA, November 2006. Selected talk.
 
Service as a Referee
 
2006
Referee for Journal of Experimental Medicine (two different manuscripts)
 
2006
Referee for Nature Medicine
 
2007 ‒ 2008
Referee for Immunity (two different manuscripts)
 
2010
Referee for Cell Host and Microbe
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Publications 
Berger M, Krebs P, Crozat K, Li X, Croker BA, Siggs OM, Popkin D, Du X, Lawson BR, Theofilopoulos AN, Xia Y, Khovananth K, Moresco EM, Satoh T, Takeuchi O, Akira S, Beutler BA. An Slfn2 mutation causes lymphoid and myeloid immunodeficiency due to loss of immune cell quiescence. (Role: I initiated the study and performed most of the experimental work.)
Nat Immunol. 11:335-43 (2010). (ISI impact factor: 25.67, ISI citation index: 8)    
·  Comments on this article:
        i.   In “News and Views section” of Nature Immunology, by Horton MR and Powell JD. “Quieting T-cells with Slfn2”. Nat Immunol. 11:281-2. (2010).
        ii.   In “Faculty of 1000”, by Flavius Martin: http://f1000biology.com/article/id/2657957
        iii.  In “Faculty of 1000”, by Dan Conrad http://f1000biology.com/article/id/2657957
 
Siggs OM, Berger M, Krebs P, Arnold CN, Eidenschenk C, Huber C, Pirie E, Smart NG, Khovananth K, Xia Y, McInerney G, Karlsson Hedestam GB, Nemazee D, Beutler BA. A mutation of Ikbkg causes immune deficiency without impairing degradation of IkappaB alpha. (Role: I performed most of the biochemical work.)
Proc Natl Acad Sci U S A. 107: 3046-51 (2010). (ISI impact factor: 9.77, ISI citation index: 5)
 
Louria-Hayon I, Alsheich-Bartok O, Levav-Cohen Y, Silberman I, Berger M, Grossman T, Matentzoglu K, Jiang YH, Muller S, Scheffner M, Haupt S, Haupt Y. E6AP promotes the degradation of the PML tumor suppressor. (Role: I performed the in-vitro ubiquitination studies.)
Cell Death Differ. 1156-66 (2009). (ISI impact factor: 9.05, ISI citation index: 11)
 
Croker BA, Lawson BR, Rutschmann S, Berger M, Eidenschenk C, Blasius AL, Moresco EM, Sovath S, Cengia L, Shultz LD, Theofilopoulos AN, Pettersson S, Beutler BA. Inflammation and autoimmunity caused by a SHP1 mutation depend on IL-1, MyD88, and a microbial trigger. (Role: I uncovered how SHP1 regulates the activation threshold of the Toll-like receptor (TLR) signalling pathway.)
Proc Natl Acad Sci U S A. 105: 15028-33 (2008). (ISI impact factor: 9.77, ISI citation index: 0)
 
Croker BA, Crozat K, Berger M, Xia Y , Sovath S, Schaffer L, Eleftherianos I, Imler JL & Beutler BA. ATP-sensitive potassium channels mediate survival during infection in mammals and insects. (Role: I defined the involvement of Kir6.1 protein in the Toll-like receptor (TLR) signalling pathway.)Nature Genet. 39: 1453 – 1460 (2007). (ISI impact factor: 36.37, ISI citation index: 15)
 
Berger M, Stahl N, Del Sal G and Haupt Y. Mutations in proline 82 of p53 uncouple its activation by Pin1 and Chk2 in response to DNA damage. (Role: I initiated the study and performed most of the experimental work.)
Mol Cell Biol. 25:5380-8 (2005). (ISI impact factor: 6.18, ISI citation index: 27)
 
Haupt S, Berger M, Goldberg Z, Haupt Y. Apoptosis – the p53 network. (Role: I wrote the paragraphs on p53-mediated apoptosis and p53 co-activators.)
J Cell Sci. 15:4077-85 (2003). (ISI impact factor: 6.29, ISI citation index: 321).
 
Goldberg Z, Vogt Sionov R, Berger M, Zwang Y, Perets R, Van Etten RA, Oren M, Taya Y, Haupt Y. Tyrosine phosphorylation of Mdm2 by c-Abl: implications for p53 regulation. (Role: I performed the cell cycle and apoptosis studies.)
EMBO J.. 21:3715-27 (2002). (ISI impact factor: 10.12, ISI citation index: 91).
 
Sionov RV, Coen S, Goldberg Z, Berger M, Bercovich B, Ben-Neriah Y, Ciechanover A, Haupt Y. c-Abl regulates p53 levels under normal and stress conditions by preventing its nuclear export and ubiquitination. (Role: I performed the flow cytometric studies and analysis.)
Mol Cell Biol. 21: 5869-78 (2001). (ISI impact factor: 6.18, ISI citation index: 54)
 
Berger M, Vogt Sionov R, Levine AJ, Haupt Y. A role for the polyproline domain of p53 in its regulation by Mdm2. (Role: I initiated the study and performed most of the experimental work).
J Biol Chem. 276:3785-90 (2000). (ISI impact factor: 5.32, ISI citation index: 28)
 
Muller S, Berger M, Lehembre F, Seeler JS, Haupt Y, Dejean A. c-Jun and p53 activity is modulated by SUMO-1 modification. (Role: I performed the flow cytometry studies and analysis.)
J Biol Chem. 275: 13321-9 (2000). (ISI impact factor: 5.32, ISI citation index: 245)
 
Sionov RV, Moallem E, Berger M, Kazaz A, Gerlitz O, Ben-Neriah Y, Oren M, Haupt Y. c-Abl neutralizes the inhibitory effect of Mdm2 on p53. (Role: I performed the in-vitro ubiquitination studies.)
J Biol Chem. 274: 8371-4 (1999). (ISI impact factor: 5.32, ISI citation index: 75)
 
Unger T, Juven-Gershon T, Moallem E, Berger M, Vogt Sionov R, Lozano G, Oren M, Haupt Y. Critical role for Ser20 of human p53 in the negative regulation of p53 by Mdm2. (Role: I designed and conducted the in-vitro assays to measure proteinprotein interactions.)
EMBO J. 18: 1805-14 (1999). (ISI impact factor: 10.12, ISI citation index: 265)
 
Book Chapter
 
Berger M, Haupt Y. Flow cytometric analysis of p53-induced apoptosis. (Role: I wrote the first draft and developed it with Prof. Haupt.)
Methods Mol Biol. 234:245-56 (2003).
 
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