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 signaling 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. 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. In addition, we are exploring ways how to exploit our findings in order to better treat leukemia and improve vaccines.
Elucidate key molecular processes maintaining
quiescence in T cells.
networks in T cells: role of mitochondria in maturation and function of T cells
Immune memory: The role of mitochondrial
membrane potential in fate decision of naïve CD8+ T cells
Cancer research: Targeting T-lymphocyte quiescence
as a novel treatment for T-ALL (T-cell acute lymphoblastic
leukemia) and other T-cell-malignancies.
Dr. Michael Berger, Head of the lab
Dr. Leonor Daniel -Cohen, Lab manager
Dr. Yuval Malka, Postdoctoral fellow
Ibrahim Omar, PhD Student
Amijai Saragovi, PhD Student
Shani Mistriel-Zerbib, PhD Student
Eliran Arbib, PhD Student
Miri Kuchersky, Msc student
Omri Yosef, project student
Dr. Antonio Lapenna, Postdoctoral fellow
Aviya Goldshtein, Msc Student
Mirit Musseri, Msc student
Eleanor Rachi, Lab technician
Beni Shlezinger, project student
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.)
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.
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.
Awarded by Keren Kayemet ‒ Jewish National Fund, from the Arthur and Ludmila Zucker Memorial Fund for Cancer Research.
Excellency in Teaching Award, Hadassah Medical School, The Hebrew University of Jerusalem, Israel.
Travel grant from NIH.
Malka Y., Steiman-Shimony A., Rosenthal E.,
Argaman L., Cohen-Daniel L., Arbib E., Margalit H., Kaplan T*., and Berger, M*. (2017) Post-transcriptional
3’UTR cleavage of mRNA transcripts generates thousands of stable uncapped
autonomous RNA fragments. Nature Communications 8, 2029, doi:
10.1038/s41467-017-02099-7. (Equal contribution with Kaplan T)
L, Jiang Z, Acosta-Rodriguez VA, Berger M, Du X, Choi JH et al. (2017)
HCFC2 is needed for IRF1- and IRF2-dependent Tlr3 transcription and for survival
during viral infections. The Journal of Experimental Medicine
3. Omar, I., Rom, O.,
Aviram, M., Cohen-Daniel, L., Gebre, AK., Parks, JS., and Berger, M. (2017) Slfn2 mutation-induced loss of T cell
quiescence leads to elevated de novo sterol synthesis. Immunology
Molho-Pessach, V., Ramot, Y.,
Mogilevsky, M., Cohen-Daniel, L., Eisenstein, E. M., Abu-Libdeh, A., Siam, I.,
Berger, M., Karni, R., and Zlotogorski, A. (2017) Generalized verrucosis
and abnormal T cell activation due to homozygous TAOK2 mutation, J
Lapenna, A., Omar, I., and Berger,
M. (2017) A novel spontaneous mutation in the TAP2 gene unravels its role
in macrophage survival, Immunology 150, 432-443.
Wang, Y., Su, L., Morin, M.
D., Jones, B. T., Whitby, L. R., Surakattula, M. M., Huang, HS.,
Shi, H., Choi, J. H., Wang, K. W., Moresco, E. M., Berger, M., Zhan, X.,
Zhang, H., Boger, D. L., and Beutler, B. (2016) TLR4/MD-2 activation by a
synthetic agonist with no similarity to LPS, Proc Natl Acad Sci U S A 113,
7. Omar, I., Lapenna, A., Cohen-Daniel, L., Tirosh, B., and Berger,
M. (2016) Schlafen2 mutation unravels a role for chronic ER stress in the
loss of T cell quiescence, Oncotarget
8. Morin, M. D., Wang, Y., Jones, B. T., Su, L., Surakattula, M.
M., Berger, M., Huang, H., Beutler, E. K., Zhang, H., Beutler, B., and
Boger, D. L. (2016) Discovery and Structure-Activity Relationships of the
Neoseptins: A New Class of Toll-like Receptor-4 (TLR4) Agonists, J Med Chem.
9. Goldshtein, A., Zerbib, S. M., Omar, I., Cohen-Daniel, L.,
Popkin, D., and Berger, M. (2016) Loss of T-cell quiescence by targeting
Slfn2 prevents the development and progression of T-ALL, Oncotarget 7, 46835- 46847.
10. Finkin, S., Yuan, D., Stein, I., Taniguchi, K., Weber, A.,
Unger, K., Browning, J. L., Goossens, N., Nakagawa, S., Gunasekaran, G.,
Schwartz, M. E., Kobayashi, M., Kumada, H., Berger, M., Pappo, O.,
Rajewsky, K., Hoshida, Y., Karin, M., Heikenwalder, M., Ben-Neriah, Y., and
Pikarsky, E. (2015) Ectopic lymphoid structures function as microniches for
tumor progenitor cells in hepatocellular carcinoma, Nat Immunol 16,
11. Benhamron, S., Pattanayak, S. P., Berger, M., and
Tirosh, B. (2015) mTOR activation promotes plasma cell differentiation and
bypasses XBP-1 for immunoglobulin secretion, Mol Cell Biol 35, 153-166.
12. Goldshtein, A., and Berger, M. (2014) Friend or foe:
can activating mutations in NOTCH1 contribute to a favorable treatment outcome
in patients with T-ALL?, Crit Rev Oncog 19, 399-404.
Sabouri, A. H., Marcondes, M.
C. G., Flynn, C., Berger, M., Xiao, N., Fox, H. S., and Sarvetnick, N.
E. (2014) TLR signaling controls lethal encephalitis in WNV-infected brain, Brain Res 1574, 84-95.
14. Tardif, V., Manenkova, Y., Berger, M., Hoebe, K., Zuo,
J.-P., Yuan, C., Kono, D. H., Theofilopoulos, A. N., and Lawson, B. R. (2013)
Critical role of transmethylation in TLR signaling and systemic lupus
erythematosus, Clin Immunol 147, 133-143.
Arnold, C. N., Barnes, M. J., Berger,
M., Blasius, A. L., Brandl, K., Croker, B., Crozat, K., Du, X.,
Eidenschenk, C., Georgel, P., Hoebe, K., Huang, H., Jiang, Z., Krebs, P., La
Vine, D., Li, X., Lyon, S., Moresco, E. M., Murray, A. R., Popkin, D. L.,
Rutschmann, S., Siggs, O. M., Smart, N. G., Sun, L., Tabeta, K., Webster, V.,
Tomisato, W., Won, S., Xia, Y., Xiao, N., and Beutler, B. (2012) ENU-induced
phenovariance in mice: inferences from 587 mutations, BMC Res Notes 5,
16. Siggs, O. M., Berger, M., Krebs, P., Arnold, C. N.,
Eidenschenk, C., Huber, C., Pirie, E., Smart, N. G., Khovananth, K., Xia, Y.,
McInerney, G., Karlsson Hedestam, G. B., Nemazee, D., and Beutler, B. (2010) A
mutation of Ikbkg causes immune deficiency without impairing degradation of
IkappaB alpha, Proc Natl Acad Sci U S
A 107, 3046-3051.
17. Berger, M., Krebs, P., Crozat, K., Li,
X., Croker, B. A., Siggs, O. M., Popkin, D., Du, X., Lawson, B. R.,
Theofilopoulos, A. N., Xia, Y., Khovananth, K., Moresco, E. M., Satoh, T.,
Takeuchi, O., Akira, S., and Beutler, B. (2010) An Slfn2 mutation causes
lymphoid and myeloid immunodeficiency due to loss of immune cell quiescence, Nat Immunol 11, 335-343.
Alsheich-Bartok, O., Levav-Cohen, Y., Silberman, I., Berger, M.,
Grossman, T., Matentzoglu, K., Jiang, Y. H., Muller, S., Scheffner, M., Haupt,
S., and Haupt, Y. (2009) E6AP promotes the degradation of the PML tumor
suppressor, Cell Death Differ 16, 1156-1166.
Croker, B. A., Lawson, B. R.,
Rutschmann, S., Berger, M., Eidenschenk, C., Blasius, A. L., Moresco, E.
M., Sovath, S., Cengia, L., Shultz, L. D., Theofilopoulos, A. N., Pettersson, S.,
and Beutler, B. A. (2008) Inflammation and autoimmunity caused by a SHP1
mutation depend on IL-1, MyD88, and a microbial trigger, Proc Natl Acad Sci U S A 105,
20. Croker, B., Crozat, K., Berger, M., Xia, Y., Sovath, S.,
Schaffer, L., Eleftherianos, I., Imler, J. L., and Beutler, B. (2007)
ATP-sensitive potassium channels mediate survival during infection in mammals
and insects, Nat Genet 39,
21. Berger, M., Stahl, N., Del Sal, G., and
Haupt, Y. (2005) Mutations in proline 82 of p53 impair its activation by Pin1
and Chk2 in response to DNA damage, Mol
Cell Biol 25, 5380-5388.
22. Haupt, S., Berger, M.,
Goldberg, Z., and Haupt, Y. (2003) Apoptosis - the p53 network, J Cell Sci 116,
23. Goldberg, Z., Vogt Sionov, R., Berger, M., Zwang, Y.,
Perets, R., Van Etten, R. A., Oren, M., Taya, Y., and Haupt, Y. (2002) Tyrosine
phosphorylation of Mdm2 by c-Abl: implications for p53 regulation, EMBO J 21, 3715-3727.
4. Sionov, R. V., Coen, S., Goldberg, Z., Berger, M.,
Bercovich, B., Ben-Neriah, Y., Ciechanover, A., and Haupt, Y. (2001) c-Abl
regulates p53 levels under normal and stress conditions by preventing its
nuclear export and ubiquitination, Mol
Cell Biol 21, 5869-5878.
25. Berger, M., Vogt Sionov, R., Levine, A.
J., and Haupt, Y. (2001) A role for the polyproline domain of p53 in its
regulation by Mdm2, J Biol Chem
26. Muller, S., Berger,M., Lehembre, F., Seeler, J. S.,
Haupt, Y., and Dejean, A. (2000) c-Jun and p53 activity is modulated by SUMO-1
modification, J Biol Chem 275, 13321-13329.
27. Unger, T.,Juven-Gershon, T., Moallem, E., Berger, M.,
Vogt Sionov, R., Lozano, G., Oren, M., and Haupt, Y. (1999) Critical role for
Ser20 of human p53 in the negative regulation of p53 by Mdm2, EMBO J 18, 1805-1814.
28. Sionov, R. V., Moallem, E., Berger, M., Kazaz, A.,
Gerlitz, O., Ben-Neriah, Y., Oren, M., and Haupt, Y. (1999) c-Abl neutralizes
the inhibitory effect of Mdm2 on p53, J
Biol Chem 274, 8371-8374.
erger M, Haupt Y. Flow cytometric analysis of p53-induced apoptosis. Methods Mol Biol. 234:245-56 (2003).