Cancer, Chromatin, Epigenetics, Gene Regulation, Molecular Biology, Stem Cells
Cancer Biology [CAB]
PhD, SUNY Stony Brook/Cold Spring Harbor Laboratory
, The Rockefeller University
Irma T. Hirschl Charitable Trust Research Award
Tisch Cancer Institute Developmental Fund Award
Mount Sinai School of Medicine
New Scholar Award
Ellison Medical Foundation
Research Scholar Award
American Skin Association
National Science Foundation Postdoctoral Fellowship
Specific Clinical/Research Interest: Our focus is on epigenetic regulation of gene expression in multiple biological pathways including cancer (melanoma and breast cancer), cellular senescence and stem cell biology. This includes various mechanisms that alter the chromatin template, including histone modifications, histone variants and their dedicated chaperones, and non-coding RNAs.
Postdoctoral Fellows: Chiara Vardabasso, Alexandre Gaspar Maia, Dan Hasson, Thomas Strub, Flavia Ghiraldini
Current Students: Chi-Yeh (Jay) Chung (GGS), Zulekha A. Qadeer (CAB), David Valle Garcia (exchange student), Zhen Sun (DSCB)
Research Assistant: Nicholas Mills
Summary of Current Research
Chromatin is the complex of DNA and its intimately associated proteins -with histones constituting the major component. This template is an attractive candidate for shaping the features of a cell's epigenetic landscape. Disruption of a cell's epigenetic balance can perturb chromatin structure and gene regulation, contributing to disease states.
Our work focuses on the study of histone variant proteins. When incorporated into chromatin, histone variants participate in diverse nuclear functions including centromeric regulation, DNA damage responses, transcriptional activation and repression, and play a role in epigenetic inheritance of chromatin states. Histone variants alter the structure and stability of the nucleosome, and provide the cell with the potential to change its post-translational modification (PTM) profile due to amino acid sequence differences from their conventional histone counterparts. We are interested in variant-specific PTMs and their binding proteins, as well as the chaperones that escort these proteins in and out of the chromatin template. We have uncovered a critical suppressive role for the histone variant macroH2A in the progression of malignant melanoma. In addition to acting as a barrier to melanoma growth and metastasis, we reported that macroH2A also acts as a barrier to induced pluripotency by repressing a set of genes required for the early stages of reprogramming.
The Polycomb Group (PcG) proteins are also focus of the lab. In mammals, there are five homologs of the single Drosophila Pc protein and it has been a longstanding goal to understand the consequences of such expansion and diversification of this protein family in both development and disease. We have previously demonstrated that each individual Pc protein is unique not only in its histone binding-specificity, but also in its association with heterochromatin (in particular, the inactive X chromosome in female mammals). Recently, we identified Cbx7 as the primary Polycomb protein expressed in ESCs, which is important for maintaining pluripotency. We have also identified novel PTMs of Cbx family members.
Our long-term goal is to understand the chromatin changes that take place at the molecular level during the transformation process of 'normal cells' to 'cancer cells' and during the reprogramming of somatic cells to stem cells. We currently have studies underway (targeted and unbiased) to identify new players in the epigenetic regulation of melanoma progression and drug resistance to targeted therapies, as these processes remain poorly understood. We are also investigating the role of histone chaperone mutations in the context of pediatric tumor biology.
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Vardabasso C, Gaspar-Maia A, Hasson D, Pünzeler S, Valle-Garcia D, Straub T, Keilhauer EC, Strub T, Dong J, Panda T, Chung CY, Yao JL, Singh R, Segura MF, Fontanals-Cirera B, Verma A, Mann M, Hernando E, Hake SB, Bernstein E. Histone Variant H2A.Z.2 Mediates Proliferation and Drug Sensitivity of Malignant Melanoma. Molecular cell 2015 Jul; 59(1).
Duarte LF, Young AR, Wang Z, Wu HA, Panda T, Kou Y, Kapoor A, Hasson D, Mills NR, Ma'ayan A, Narita M, Bernstein E. Histone H3.3 and its proteolytically processed form drive a cellular senescence programme. Nature communications 2014; 5.
Wu HA, Balsbaugh JL, Chandler H, Georgilis A, Zullow H, Shabanowitz J, Hunt DF, Gil J, Peters G, Bernstein E. Mitogen-activated protein kinase signaling mediates phosphorylation of polycomb ortholog Cbx7. The Journal of biological chemistry 2013 Dec; 288(51).
Vardabasso C, Hasson D, Ratnakumar K, Chung CY, Duarte LF, Bernstein E. Histone variants: emerging players in cancer biology. Cellular and molecular life sciences : CMLS 2013 May;.
Gaspar-Maia A, Qadeer ZA, Hasson D, Ratnakumar K, Adrian Leu N, Leroy G, Liu S, Costanzi C, Valle-Garcia D, Schaniel C, Lemischka I, Garcia B, Pehrson JR, Bernstein E. MacroH2A histone variants act as a barrier upon reprogramming towards pluripotency. Nature communications 2013 Mar; 4.
Ratnakumar K, Duarte LF, Leroy G, Hasson D, Smeets D, Vardabasso C, Bönisch C, Zeng T, Xiang B, Zhang DY, Li H, Wang X, Hake SB, Schermelleh L, Garcia BA, Bernstein E. ATRX-mediated chromatin association of histone variant macroH2A1 regulates α-globin expression. Genes & development 2012; 26: 433-438.
Chicas A, Kapoor A, Wang X, Aksoy O, Evertts AG, Zhang MQ, Garcia BA, Bernstein E, Lowe SW. H3K4 demethylation by Jarid1a and Jarid1b contributes to retinoblastoma-mediated gene silencing during cellular senescence. Proceedings of the National Academy of Sciences of the United States of America 2012 Jun; 109(23).
O'Loghlen A, Muñoz-Cabello AM, Gaspar-Maia A, Wu HA, Banito A, Kunowska N, Racek T, Pemberton HN, Beolchi P, Lavial F, Masui O, Vermeulen M, Carroll T, Graumann J, Heard E, Dillon N, Azuara V, Snijders AP, Peters G, Bernstein E, Gil J. MicroRNA regulation of Cbx7 mediates a switch of Polycomb orthologs during ESC differentiation. Cell stem cell 2012 Jan; 10(1).
Kapoor A, Goldberg M, Cumberland L, Ratnakumar K, Segura M, Emanuel P, Menendez S, Vardabasso C, LeRoy G, Vidal C, Polsky D, Osman I, Garcia B, Hernando E, Bernstein E. The histone variant macroH2A suppresses melanoma progression through regulation of CDK8. Nature 2010; 468: 1105-1109.
Bernstein E, Muratore-Schroeder TL, Diaz RL, Chow JC, Changolkar LN, Shabanowitz J, Heard E, Pehrson JR, Hunt DF, Allis CD. A phosphorylated subpopulation of the histone variant macroH2A1 is excluded from the inactive X chromosome and enriched during mitosis. Proc Natl Acad Sci USA 2008; 105: 1533-1538.
Whitcomb SJ, Basu A, Allis CD, Bernstein E. Polycomb Group Proteins: an evolutionary perspective. Trends in Genetics 2007; 23: 494-502.
Ooi S, Qiu C, Bernstein E, Li K, Dia D, Yang Z, Erdjument-Bromage H, Tempst P, Lin S, Allis CD, Cheng X, Bestor TH. DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature 2007; 448: 714-717.
Goldberg AD, Allis CD, Bernstein E. Epigenetics: a landscape takes shape.. Cell (essay) 2007; 128: 635-638.
Bernstein E, Duncan EM, Masui O, Gil J, Heard E, Allis CD. Mouse Polycomb proteins bind differentially to methylated histone H3 and RNA and are enriched in facultative heterochromatin. Molecular and Cellular Biology 2006; 26: 2560-2569.
Bernstein E, Kim SY, Carmell MA, Murchison EP, Alcorn H, Li MZ, Mills AA, Elledge SJ, Anderson KV, Hannon GJ. Dicer is essential for mouse development. Nature Genetics 2003; 35: 5215-5217.
Paddison PJ, Caudy AA, Bernstein E, Hannon GJ, Conklin DS. Short hairpin RNAs (shRNAs) induce sequence-specific silencing in mammalian cells. Genes & Development 2002; 16: 948-958.
Ketting RF, Fischer SJ, Bernstein E, Sijen T, Hannon GJ, Plasterk RA. Dicer functions in RNA interference and in synthesis of small RNA involved in developmental timing in C. elegans. Genes & Development; 15: 2654-2695.
Bernstein E, Caudy AA, Hammond SM, Hannon GJ. Role for a bidentate nuclease in the initiation step of RNA interference. Nature 2001; 409: 363-366.
Hammond SM, Bernstein E, Beach D, Hannon GJ. An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophila cells. Nature 2000; 404: 293-296.
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