Bradley Bernstein, MD, PhD

Bernstein Lab

The Bradley Bernstein pathology research lab at Massachusetts General Hospital applies high-throughput, sequencing-based technologies to characterize chromatin structure genome-wide in human and mouse.

Overview

Bradley Bernstein, M.D., Ph.D.

Bernard and Mildred Kayden Endowed MGH Research Institute Chair
Professor of Pathology, Harvard Medical School
Pathologist, Massachusetts General Hospital
Institute Member, Broad Institute
American Cancer Society Research Professor

Massachusetts General Hospital
185 Cambridge Street
Simches Research Building CPZN 8234
Boston, MA 02114
Phone: 617-726-6906
Fax: 617-643-3566
Email: 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.

 

Geometric shapes with fluorescense imaging picturesPathology research report

 

Group Members

Members of the Bernstein Laboratory

Yotam Drier, PhD,  Research Fellow, MGH
Russell J.H. Ryan, MD,  Clinical and Research Fellow in Pathology, MGH
Efrat Shema, PhD  Research Fellow, MGH
Ik Soo Kim, PhD  Research Fellow, MGH
Cem Sievers, PhD  Research Fellow, MGH
Peter van Galen, PhD  Research Fellow, MGH
Will Flavahan, PhD  Research Fellow, MGH
Sarah Johnstone, M.D., PhD,  Clinical & Research Fellow, MGH
Anuraag Parikh, MD
Sidharth Puram, MD., PhD  Resident, Department of Otolaryngology
Volker Hovestadt, PhD  Research Fellow, MGH
Hironori Matsunaga, PhD  Visiting Researcher, MGH
Dan Tarjan, PhD Candidate, Harvard BBS
Sarah Shareef, MD/PhD student in Harvard-MIT MD/PhD Program
Fadi Najm, PhD Student, Harvard BBS
Ryanne Boursiquot Laboratory Coordinator, MGH
Elizabeth Gaskell  Scientific Advisor, Broad Institute
Dylan Rausch Research Technician II

Esmat Hegazi Research Technician I

 

Research Projects

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.

Selected Publications

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.

 

Contact

Contact Us

Bernstein Laboratory

Massachusetts General Hospital

185 Cambridge Street, CPZN 8234Richard B. Simches Research Building Boston, MA 02114
  • Phone: 617-726-6906
  • Fax: 617-643-3566

Email: bernstein.bradley@mgh.harvard.edu

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