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Bradley Bernstein, M.D., Ph.D.
Bernard and Mildred Kayden Endowed MGH Research Institute ChairProfessor of Pathology, Harvard Medical SchoolPathologist, Massachusetts General HospitalInstitute Member, Broad InstituteAmerican Cancer Society Research Professor
Massachusetts General Hospital185 Cambridge StreetSimches Research Building CPZN 8234Boston, MA 02114Phone: 617-726-6906Fax: 617-643-3566Email: Bernstein.Bradley@mgh.harvard.edu
The Bernstein laboratory studies epigenetics — changes in gene activity governed by influences outside the genes themselves — and specifically how modifications to the protein scaffold called chromatin contribute to mammalian development and human cancer. His laboratory develops genomic technologies to study chromatin structure and epigenetic regulation. The work is notable for the discovery of epigenetic mechanisms in stem cells, the annotation of thousands of enhancer ‘switches’ in the human genome relevant to common disease, and the characterization of epigenetic lesions that drive brain tumors and other forms of cancer.Our long-term goal is to achieve a more complete understanding of how epigenetic alterations lead to cancer and other diseases, and how these may be corrected by ‘epigenetic’ or other targeted therapies.
Technologies for mapping histone modifications and chromatin proteins
We are combining tools in stem cell biology, biochemistry and genome engineering with next-generation sequencing to achieve increasingly precise, genome-wide views of chromatin structure, chromatin regulator binding and genome organization. Genetic and chemical perturbations then allow us to test predicted regulatory interactions and functions. Ongoing projects are applying these approaches to characterize noncoding regulatory elements in the human genome and to understand how the resulting cell circuits control gene expression programs during development and in cancer. We also leverage emerging single-cell and single-molecule techniques to deconvolve heterogeneous cell populations and dynamic processes.
Epigenetic regulation of stem cell differentiation Chromatin regulators play critical roles in controlling the expression and potential of genes during development. We identified a novel chromatin structure, termed bivalent domains, that is subject to simultaneous regulation by Polycomb repressors and trithorax activators. In ES cells, bivalent domains appear to keep developmental genes poised for alternate fates. We are now applying emerging chromatin and genome engineering approaches to study how bivalent domains and interacting regulatory elements program gene expression in development.
Chromatin regulation in cancer cells Genes encoding chromatin regulators are frequently mutated in human cancer. Moreover, cells in an individual tumor can vary markedly in their epigenetic states, transcriptional outputs, and functional phenotypes. We seek to understand how epigenetic lesions and epigenetic heterogeneity contribute to key cancer cell properties, such as tumor propagation, stemness, and drug resistance. We characterize the transcriptional and epigenetic landscapes of primary tumors and, in parallel, investigate representative tumor models in the laboratory. These synergistic approaches can inform therapeutic strategies for targeting epigenetic lesions or overcoming resistance mechanisms.
Read more on Dr. Bernstein's research lab website at http://bernstein.mgh.harvard.edu/.
Read more about the Bernstein Lab from the Center for Cancer Research Annual Report and the Pathology Basic Science Research Brochure.
Members of the Bernstein Laboratory
Yotam Drier, PhD, Research Fellow, MGHRussell J.H. Ryan, MD, Clinical and Research Fellow in Pathology, MGHEfrat Shema, PhD Research Fellow, MGHIk Soo Kim, PhD Research Fellow, MGHCem Sievers, PhD Research Fellow, MGHPeter van Galen, PhD Research Fellow, MGHWill Flavahan, PhD Research Fellow, MGHSarah Johnstone, M.D., PhD, Clinical & Research Fellow, MGHAnuraag Parikh, MDSidharth Puram, MD., PhD Resident, Department of OtolaryngologyVolker Hovestadt, PhD Research Fellow, MGHHironori Matsunaga, PhD Visiting Researcher, MGHDan Tarjan, PhD Candidate, Harvard BBSSarah Shareef, MD/PhD student in Harvard-MIT MD/PhD ProgramFadi Najm, PhD Student, Harvard BBSRyanne Boursiquot Laboratory Coordinator, MGHElizabeth Gaskell Scientific Advisor, Broad InstituteDylan Rausch Research Technician II
Esmat Hegazi Research Technician I
Current projects in the lab are focused on the 'bivalent' domains of chromatin 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. Read more about the Bernstein pathology research lab.
Bibliography of Bradley Bernstein on PubMed
Flavahan WA, Drier Y, Liau BB, Gillespie SM, Venteicher AS, Stemmer-Rachamimov AO, Suva ML, Bernstein BE. Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature. 2016; 529:110-4.
Shema E, Jones D, Shoresh N, Donohue L, Ram O, Bernstein BE. Single-molecule decoding of combinatorially modified nucleosomes. Science. 2016; 352:717-21.
Suva ML, Rheinbay E, Gillespie SM, Wakimoto H, Cahill DP, Nashed BV, Curry WT, Martuza RL, Louis DN, Rozenblatt-Rosen O, Suva ML, Regev A Bernstein BE. Reconstructing and programming the tumor propagating potential of glioblastoma stem-like cells. Cell. 2014; 157: 580-594. .
Patel AP, Tirosh I, Trombetta JJ, Shalek AK, Gillespie SM, Wakimoto H, Cahill DP, Nahed BV, Curry WT, Martuza RL, Louis DN, Rozenblatt-Rosen O, Suva ML, Regev A, Bernstein BE. Single Cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science. 2014; 344:1396-1401.
Suva ML, Riggi N, Bernstein BE. Epigenetic reprogramming in cancer. Science. 2013; 339:1567-70.
Ernst J, Kheradpour P, Mikkelsen TS, Shoresh N, Ward LD, Epstein CB, Zhang X, Wang L, Issner R, Coyne M, Ku M, Durham T, Kellis M, Bernstein BE. Mapping and analysis of chromatin state dynamics in nine human cell types. Nature. 2011; 473:43-9.
Massachusetts General Hospital
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