Epigenetic states are flexible yet persist through multiple cell divisions and exert powerful effects on normal and abnormal cellular phenotypes. We are interested in understanding the mechanistic basis for epigenetic regulation; both during normal development as well as in cancer. Our research focuses on two major topics: the role of epigenetics in the development of the immune system, and its involvement in stem cells and cancer.
Programming of allelic exclusion
Although mammals clearly benefit from the fact that they are diploid, over 10% of the genome is actually expressed monoallelically in a non-imprinted manner. This includes olfactory receptor selection, X-inactivation in females, ribosomal RNA regulation, and allelic exclusion in the immune system. One of the cornerstones of immunology is that mature antigen receptors are only produced from a single allele in each cell, a phenomenon termed allelic exclusion. Very little is known about how this phenomenon is regulated and programmed during development. We have demonstrated that allelic choice takes place in a programmed manner. The main proof for this mode of action is based on the observation that the two immunoglobulin-kappa alleles can already be distinguished by a number of different epigenetic marks prior to the recombination reaction. These markings include; histone modification, nuclear localization, replication timing and DNA methylation (Mostoslavsky et al, Nature 2001; Goldmit et al., Nature Immunology, 2005; Fraenkel et al., Nature Immunology, 2006; Farago et al., Nature 2012). These findings form the basis for our current studies.
1. We are interested in deciphering the role of DNA methylation, histone modification, nuclear compartmentalization of chromatin domains, replication timing, long range interactions, and the B lineage specification and commitment transcriptional network in preserving allele-specific structure. In this way, we will understand how immunoglobulin kappa locus allelic exclusion is established during lymphoid development in a clonal manner, such that one allele in each cell has a closed structure while the other allele is in an epigenetically open conformation that allows it to undergo rearrangement.
2. Recently, we demonstrated for the first time that while individual hematopoietic stem cells are characterized by allelic plasticity, early lymphoid lineage cells become committed to the choice of a single allele and this decision is then stably maintained in a clonal manner that predetermines monoallelic rearrangement in B cells. This is accompanied at the molecular level by underlying allelic changes in asynchronous replication timing patterns at the kappa locus, which outline a completely new concept as to how the production of antigen receptors is regulated in the immune cell (Farago et al., Nature 2012). Our aim is to study the molecular mechanisms that underlie allelic plasticity in embyonal and adult stem cells, a hallmark of stem cell biology.
The role of histone and DNA methylation in stem cells and cancer
Long-term repression plays an important part in the programming of gene expression profiles in the developing organism. We have clearly demonstrated that the histone methylase G9a is a master structural regulator that plays an important role in early development by targeting a wide network of embryonic genes for post-implantation repression. This silencing process includes key genes, such as Oct-3/4, Nanog and Dnmt3L (Feldman et al., Nature Cell Biology, 2006; Epsztein-Litman et al., Nature Structural and Molecular Biology, 2008). Tumor properties are largely determined by the balance between the stem cell state, with its self-renewal capacity and phenotypic plasticity, and the inherent program that directs these cells to undergo differentiation. This balance is largely controlled by epigenetic regulators.
1. We are interested in studying the molecular mechanisms by which epigenetic regulators execute gene expression changes to control cancer cell differentiation state. Specifically, we will decipher how changes in the activity of chromatin regulators influence chromatin structure throughout the genome, and how these factors actually regulate the establishment of cancer specific methylation states.
2. Many studies have shown that cancer cells are subjected to abnormal de novo DNA methylation compared with their normal counterparts. Furthermore, it was shown that methylation occurs through a programmed mechanism that targets specific genes. Moreover recent findings show that chronic inflammation, which is now an established cancer risk factor, is associated with aberrant DNA methylation as well. Our team is performing a comprehensive analysis that could help decipher the rules that govern this process of de novo methylation on a genome-wide basis, as well as understanding the molecular mechanisms that underlie this process. We will study how upstream signaling pathways regulate global de novo methylation in inflammation and cancer. Since this mechanism is characteristic of many types of tumors, it would potentially lead to a better understanding of cancer, and, hopefully, to a treatment across a wide spectrum of cancers.
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Farago M, Rosenbluh C, Tevlin M, Fraenkel S, Schlesinger S, Masika H, Gouzman M, Teng G, Schatz D, Rais Y, Hanna JH, Mildner A, Jung S, Mostoslavsky G, Cedar H, Bergman Y. Clonal allelic predetermination of immunoglobulin-κ rearrangement. Nature. 2012 Oct 25;490(7421):561-5
Abu-Remaileh M, Gerson A, Farago M, Nathan G, Alkalay I, Zins Rousso S, Gur M, Fainsod A, Bergman Y. Oct-3/4 regulates stem cell identity and cell fate decisions by modulating Wnt/β-catenin signalling. EMBO J. 2010 Oct 6;29(19):3236-48
Gielchinsky Y, Laufer N, Weitman E, Abramovitch R, Granot Z, Bergman Y, Pikarsky E. Pregnancy restores the regenerative capacity of the aged liver via activation of an mTORC1-controlled hyperplasia/hypertrophy switch. Genes Dev. 2010 Mar 15;24(6):543-8
Schlesinger S, Selig S, Bergman Y, Cedar H. Allelic inactivation of rDNA loci. Genes Dev. 2009 Oct 15;23(20):2437-47
Epsztejn-Litman S, Feldman N, Abu-Remaileh M, Shufaro Y, Gerson A, Ueda J, Deplus R, Fuks F, Shinkai Y, Cedar H, Bergman Y. De novo DNA methylation promoted by G9a prevents reprogramming of embryonically silenced genes. Nat Struct Mol Biol. 2008 Nov;15(11):1176-83
Fraenkel S, Mostoslavsky R, Novobrantseva TI, Pelanda R, Chaudhuri J, Esposito G, Jung S, Alt FW, Rajewsky K, Cedar H, Bergman Y. Allelic 'choice' governs somatic hypermutation in vivo at the immunoglobulin kappa-chain locus. Nat Immunol. 2007 Jul;8(7):715-22
Schlesinger Y, Straussman R, Keshet I, Farkash S, Hecht M, Zimmerman J, Eden E, Yakhini Z, Ben-Shushan E, Reubinoff BE, Bergman Y, Simon I, Cedar H. Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat Genet. 2007 Feb;39(2):232-6
Feldman N, Gerson A, Fang J, Li E, Zhang Y, Shinkai Y, Cedar H, Bergman Y. G9a-mediated irreversible epigenetic inactivation of Oct-3/4 during early embryogenesis. Nat Cell Biol. 2006 Feb;8(2):188-94
Goldmit M, Ji Y, Skok J, Roldan E, Jung S, Cedar H, Bergman Y. Epigenetic ontogeny of the Igk locus during B cell development. Nat Immunol. 2005 Feb;6(2):198-203
Gidekel S, Pizov G, Bergman Y, Pikarsky E. Oct-3/4 is a dose-dependent oncogenic fate determinant. Cancer Cell. 2003 Nov;4(5):361-70. PubMed PMID: 14667503.
Ji Y, Zhang J, Lee AI, Cedar H, Bergman Y. A multistep mechanism for the activation of rearrangement in the immune system. Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7557-62
Singh N, Bergman Y, Cedar H, Chess A. Biallelic germline transcription at the kappa immunoglobulin locus. J Exp Med. 2003 Mar 17;197(6):743-50
Goldmit M, Schlissel M, Cedar H, Bergman Y. Differential accessibility at the kappa chain locus plays a role in allelic exclusion. EMBO J. 2002 Oct 1;21(19):5255-61
Gidekel S, Bergman Y. A unique developmental pattern of Oct-3/4 DNA methylation is controlled by a cis-demodification element. J Biol Chem. 2002 Sep 13;277(37):34521-30. Epub 2002 Jul 10. PubMed PMID: 12110668.
Mostoslavsky R, Singh N, Tenzen T, Goldmit M, Gabay C, Elizur S, Qi P, Reubinoff BE, Chess A, Cedar H, Bergman Y. Asynchronous replication and allelic exclusion in the immune system. Nature. 2001 Nov 8;414(6860):221-5
Mostoslavsky, R. Singh, N., Kirillov, A., Pelanda, R., Cedar, H., Chess, A. and Bergman, Y. (1998) chain monoallelic demethylation and the establishment of allelic exclusion. Genes and Development 12:1801-1811.
Kirillov, A., Kistler, B., Mostoslavsky, R., Cedar, H., Wirth, T. and Bergman, Y. (1996) A role for nuclear NF-B in B-cell-specific demethylation of the Ig locus. Nature Genetics 13: 435-441.
Lichtenstein M, Keini G, Cedar H, Bergman Y. B cell-specific demethylation: a novel role for the intronic kappa chain enhancer sequence. Cell. 1994 Mar 11;76(5):913-23.
Ben-Shushan, E., Pikarsky, E., Klar, A. and Bergman, Y. (1993) Extinction of Oct-3/4 gene expression in EC x fibroblast somatic cell hybrids is accompanied by changes in the methylation status, chromatin structure and transcriptional activity of the Oct-3/4 upstream region. Mol. Cell. Biol. 13: 891-901.
Pikarsky, E., Sharir, H., Ben-Shushan, E. and Bergman, Y. (1994) Retinoic acid represses Oct-3/4 gene expression through several retinoic acid responsive elements located in the promoter-enhancer regions. Mol. Cell. Biol. 14:1026-1038.
Bergman Y, Cedar H. DNA methylation dynamics in health and disease. Nat Struct Mol Biol. 2013 Mar;20(3):274-81. doi: 10.1038/nsmb.2518
Cedar H, Bergman Y. Programming of DNA methylation patterns. Annu Rev Biochem. 2012;81:97-117. doi: 10.1146/annurev-biochem-052610-091920
Cedar H, Bergman Y. Epigenetics of haematopoietic cell development. Nat Rev Immunol. 2011 Jun 10;11(7):478-88. doi: 10.1038/nri2991
Bergman Y, Cedar H. Epigenetic control of recombination in the immune system. Semin Immunol. 2010 Dec;22(6):323-9
Cedar H, Bergman Y. Linking DNA methylation and histone modification: patterns and paradigms. Nat Rev Genet. 2009 May;10(5):295-304
Cedar H, Bergman Y. Choreography of Ig allelic exclusion. Curr Opin Immunol. 2008 Jun;20(3):308-17
Fraenkel S, Bergman Y. Variability and exclusion in host and parasite: epigenetic regulation of Ig and var expression. J Immunol. 2006 Nov 1;177(9):5767-74
Bergman Y, Cedar H. A stepwise epigenetic process controls immunoglobulin allelic exclusion. Nat Rev Immunol. 2004 Oct;4(10):753-61
Goldmit M, Bergman Y. Monoallelic gene expression: a repertoire of recurrent themes. Immunol Rev. 2004 Aug;200:197-214
Bergman Y, Fisher A, Cedar H. Epigenetic mechanisms that regulate antigen receptor gene expression. Curr Opin Immunol. 2003 Apr;15(2):176-81
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