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Research at Mass General
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
In the Bernstein laboratory we study 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. Our laboratory develops genomic technologies to study chromatin structure and epigenetic regulation. Our 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.
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 at the single cell level. In parallel, we develop and perturb representative tumor models in the laboratory. These synergistic approaches can inform therapeutic strategies for targeting epigenetic lesions or overcoming resistance mechanisms.
We innovate and combine technologies in stem cell biology, biochemistry, imaging, 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 apply these approaches to characterize noncoding regulatory elements and chromatin structure in the human genome and to understand how the resulting cell circuits control gene expression programs during development and in cancer. We also develop and leverage emerging single-cell and single-molecule techniques to deconvolve heterogeneous cell populations and dynamic processes in tumors.
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 now apply emerging chromatin and genome engineering approaches to study how bivalent domains and interacting regulatory elements program gene expression in development.
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.
Members of the Bernstein Laboratory
Bradley Bernstein, MD, PhD Yotam Drier, PhD Will Flavahan, PhD Sarah Johnstone, MD, PhD Ik Soo Kim, PhD Fadi Najm, BSAnuraag Parikah, MD Sid Purham, MD, PhD Dylan Rausch, BS Russel Ryan, MD Sarah Shareef, BS* Efrat Shema-Yaacoby, PhD Cem Sievers, PhD Dan Tarjan, BS* Peter van Galen, PhD Hironori Matsunaga, PhDEsmat Hegazi, BS
A central question in human biology is how a single genome sequence can give rise to the hundreds of different cell types in the body. Scientists understand that differential patterns of gene expression underlie the many different cellular phenotypes seen in multicellular organisms. However, our understanding of how these gene expression patterns arise during development and how they are subsequently maintained in the adult organism remains poor. A number of studies have indicated that these different expression patterns and phenotypes are intimately related to the way in which genomic DNA is organized into chromatin in the cell. This organizational structure of proteins and DNA, sometimes referred to as the epigenome, helps control which genes are expressed in a given cell type and is critical to the function of normal cells. Moreover, a large body of evidence suggests that the epigenome is inappropriately altered in most—if not all—human cancers.
The long-term goal of our research is to achieve a comprehensive understanding of how the human genome is organized into chromatin. Our group is further focused on understanding how dynamic alterations in chromatin structure contribute to mammalian development and how aberrant chromatin regulation contributes to cancer progression, heterogeneity and therapeutic resistance. We are taking a multifaceted approach involving stem cell biology, biochemistry genetics, genomics and computational biology. The specific areas of research activity in the lab are explained below.
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
Insulator dysfunction and oncogene activation in IDH mutant gliomas.
Flavahan WA, Drier Y, Liau BB, Gillespie SM, Venteicher AS, Stemmer-Rachamimov AO, Suvà ML, Bernstein BE. Nature. 2016 Jan 7;529(7584):110-4.
Single-molecule decoding of combinatorially modified nucleosomes. Shema E, Jones D, Shoresh N, Donohue L, Ram O, Bernstein BE. Science. 2016 May 6;352(6286):717-21.
Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells. Suvà ML, Rheinbay E, Gillespie SM, Patel AP, Wakimoto H, Rabkin SD, Riggi N, Chi AS, Cahill DP, Nahed BV, Curry WT, Martuza RL, Rivera MN, Rossetti N, Kasif S, Beik S, Kadri S, Tirosh I, Wortman I, Shalek AK, Rozenblatt-Rosen O, Regev A, Louis DN, Bernstein BE. Cell. 2014 Apr 24;157(3):580-94.
Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. 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, Suvà ML, Regev A, Bernstein BE. Science. 2014 Jun 20;344(6190):1396-401.
Puram SV, Tirosh I, Parikh AS, Patel AP, Yizhak K, Gillespie S, Rodman C, Luo CL, Mroz EA, Emerick KS, Deschler DG, Varva- res MA, Mylvaganam R, Rozenblatt-Rosen O, Rocco JW, Faquin WC, Lin DT, Regev A, Bernstein BE. Single-Cell Transcriptomic Analysis of Primary and Metastatic Tumor Ecosystems in Head and Neck Cancer. Cell. 2017; 171(7):1611-1624.e24.
Flavahan WA, Gaskell E, Bernstein BE. Epigenetic plasticity and the hallmarks of cancer. Science. 2017; 357(6348).
Liau BB, Sievers C, Donohue LK, Gillespie SM, Flavahan WA, Miller TE, Venteicher AS, Hebert CH, Carey CD, Rodig SJ, Sha- reef SJ, Najm FJ, van Galen P, Wakimoto H, Cahill DP, Rich JN, Aster JC, Suvà ML, Patel AP, Bernstein BE. Adaptive Chromatin Remodeling Drives Glioblastoma Stem Cell Plasticity and Drug Tolerance. Cell Stem Cell. 2017; 20(2):233-246.e7.
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