Bradley Bernstein

Department of Pathology
Massachusetts General Hospital, Harvard Medical School and Broad Institute
Richard B Simches Building, CPZN 8234

185 Cambridge St.

Boston, MA 02114
Tel: 617-726-6906
Fax: 617-726-5684
Email: bernstein.bradley@mgh.harvard.edu
2 postdoctoral fellows, 1 graduate student, 1 technician

Though much of what defines a human is encoded in the sequence of our DNA, many additional factors influence how this genetic information is manifest. For example, heritable epigenetic information contained within chromatin, the higher-order structure that packages the genome, has critical functions during embryonic development and can contribute to the pathogenesis of disease. Our laboratory applies high-throughput sequencing-based technologies to characterize chromatin structure genome-wide in human and mouse. In addition to advancing technology and providing unprecedented global views of mammalian chromatin, this work has led to an appreciation of the role of large-scale chromatin structures, or ‘domains’, in regulating developmental genes. In differentiated cells, chromatin domains marked by either ‘active’ or ‘repressive’ histone modifications maintain expression or repression of key developmental genes (‘master regulators’). However, in pluripotent ES cells, chromatin domains enriched for both active and repressive modifications repress developmental genes while maintaining their potential for subsequent activation. Current projects in the lab are are focused on these 'bivalent' domains with the goals of understanding their initial establishment, their higher-order structure, and their roles in ES cell pluripotency and epigenetic regulation. Similar approaches are also being used to characterize chromatin modifications in adult stem cells and cancer models. Our long-term goal is to achieve a systems level understanding of chromatin regulation during development, and how chromatin mis-regulation contributes to human disease.

References:

• Ku M, Koche RP, Rheinbay E, Mendenhall EM, Endoh M, Mikkelsen TS, Presser A, Nusbaum C, Xie X, Chi A, Adli M, Kasif S, Ptaszek LM, Cowan CA, Lander ES, Koseki H, Bernstein BE. Genomewide Analysis of PRC1 and PRC2 Occupancy Identifies Two Classes of Bivalent Domains. PLOS Genetics 2008; 4:e1000242.
• Mikkelsen TS, Ku M, Jaffe DB, Issac B, Lieberman E, Giannoukos G, Alvarez P, Brockman W, Kim TK, Koche RP, Lee W, Mendenhall E, O'Donovan A, Presser A, Russ C, Xie X, Meissner A, Wernig M, Jaenisch R, Nusbaum C, Lander ES, Bernstein BE. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 2007; 448:553-560.
• Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, Fry B, Meissner A, Wernig M, Plath K, Jaenisch R, Wagschal A, Feil R, Schreiber SL, Lander ES. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 2006;125:315-26.
• Bernstein BE, Kamal M, Lindblad-Toh K, Bekiranov S, Bailey DK, Huebert DJ, McMahon S, Karlsson EK, Kulbokas EJ, Gingeras TR, Schreiber SL, Lander ES. Genomic maps and comparative analysis of histone modifications in human and mouse. Cell 2005;120:169-81.
• Schreiber SL, Bernstein BE. Signaling network model of chromatin. Cell 2002;111:771-778.