- ASSISTANT PROFESSOR Oncological Sciences
- ASSISTANT PROFESSOR Dermatology
Ph.D., SUNY Stony Brook/Cold Spring Harbor Laboratory
The Rockefeller University
2012 - 2016
Irma T. Hirschl Charitable Trust Research Award
2010 - 2011
Tisch Cancer Institute Developmental Fund Award
Mount Sinai School of Medicine
2008 - 2012
New Scholar Award
Ellison Medical Foundation
2008 - 2009
Research Scholar Award
American Skin Association
2004 - 2006
National Science Foundation Postdoctoral Fellowship
ResearchSpecific Clinical/Research Interest: Our focus is on epigenetic regulation of gene expression in multiple biological pathways including cancer (focus on melanoma) 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
Current Students: Hsan-Au (Mooki) Wu, Luis F. Duarte, Chi-Yeh (Jay) Chung, Dan Hasson, Zulekha A. Qadeer
Research Assistant: Taniya Panda
Summary of Current Research
Epigenetic regulation underlies the commitment of a genomic locus or chromosome (e.g., inactive X) to a particular transcriptional state throughout differentiation and development. This regulation is mediated by various intersecting mechanisms including: histone modifications, histone-modifying enzymes, histone binding proteins, histone variants, DNA methylation, and non-coding RNAs. Epigenetics, in a broad sense, is a bridge between genotype and phenotype - a phenomenon that changes the final outcome of a locus or chromosome without changing the underlying DNA sequence. For example, although the vast majority of cells in a multicellular organism share an identical genotype, the process of development generates numerous cell types with disparate, yet stable profiles of gene expression and distinct cellular functions. Disruption of this epigenetic balance can perturb gene regulation and may lead to disease, notably cancer.
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. At the heart of epigenetic gene silencing lay histone H3K27 methylation and the Polycomb Group (PcG) proteins, which are a main 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). We are also investigating the mechanism of Pc recruitment to chromatin, as this aspect of Pc function is essentially unknown.
A second major focus in the lab is 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 potentially 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.
Finally, 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'. Recently, we have uncovered a critical role for histone variants in the progression of malignant melanoma.
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, Bernstein E. ATRX: the case of a peculiar chromatin remodeler. Epigenetics : official journal of the DNA Methylation Society 2013 Jan; 8(1).
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.
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.
El Messaoudi-Aubert S, Nicholls J, Maertens GN, Brookes S, Bernstein E, Peters G. Role for the MOV10 RNA helicase in Polycomb-mediated repression of the INK4a tumor suppressor. Nature Structural & Molecular Biology 2010; 17: 862-868.
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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Dr. Bernstein did not report having any of the following types of financial relationships with industry during 2012 and/or 2013: consulting, scientific advisory board, industry-sponsored lectures, service on Board of Directors, participation on industry-sponsored committees, equity ownership valued at greater than 5% of a publicly traded company or any value in a privately held company. Please note that this information may differ from information posted on corporate sites due to timing or classification differences.
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