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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
The Bernstein laboratory studies how the DNA in the human genome is packaged by a structure called chromatin. A central question in human biology is how the one genome we inherit at birth can give rise to the hundreds of cell types in the body. The genome consists of genes that code for the protein machines in our cells as well as regulatory elements that control those genes. A liver cell is different from an immune cell or a neuron because it makes different proteins. The way a gene is organized into chromatin predicts whether it will be turned on or off—and thus make protein—in a particular cell type. Our lab has identified specific types of chromatin that help determine when certain genes are on or off or that keep a gene poised to be turned on later in development. We leverage emerging technologies in genomics and computation to study chromatin organization across the genome. We use this information to better understand chromatin regulatory processes and how their failure contributes to cancer.
Technologies for mapping histone modifications and chromatin proteins
We are combining tools in cell biology, biochemistry and molecular biology with next-generation sequencing to achieve increasingly precise, genome-wide views of chromatin structure, chromatin regulator binding and genome organization. Integrative analysis of such chromatin state maps yields detailed annotations of the locations and dynamics of functional elements in the human genome, including promoters, transcripts, silencers, insulators and enhancers. Ongoing projects are applying these annotations to understanding cell circuits and how they vary across cell types during development and in cancer.
Epigenetic regulation of stem cell differentiation
Chromatin regulators, such as the Polycomb and trithorax complexes, 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. Bivalent domains appear to keep developmental regulator genes poised in pluripotent embryonic stem cells and may also serve similar functions in multipotent progenitor cells. Current studies are leveraging a new generation of experimental assays to characterize the functions of bivalent domains and to understand the mechanisms that underlie their establishment and function.
Chromatin regulation in cancer cells
Genes encoding chromatin regulators are frequently mutated in human cancer. In specific cases, these alterations appear to be major drivers of the malignant state. Ongoing studies in the lab seek to apply epigenomic technologies to characterize the transcriptional and epigenetic landscapes of cancer stem cells and to identify mechanisms by which epigenetic changes contribute to therapeutic resistance.
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
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
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. 157: 580-594, 2014.
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. 344:1396-1401, 2014.
Knoechel B, Roderick JE, Williamson KE, Zhu J, Lohr JG, Cotton MJ, Gillespie SM, Fernandez D, Ku M, Wang H, Piccioni F, Silver SJ, Jain M, Pearson D, Kluk MJ, Ott CJ, Shultz LD, Brehm MA, Greiner DL, Gutierrez A, Stegmaier K, Kung AL, Root DE, Bradner JE, Aster JC, Kelliher MA, Bernstein BE. An epigenetic mechanism of resistance to targeted therapy in T-cell acute lymphoblastic leukemia. Nat Genet. 46: 364-70, 2014.
Suva ML, Riggi N, Bernstein BE. Epigenetic reprogramming in cancer. Science. 339:1567-70, 2013.
Massachusetts General Hospital
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