Bernstein Lab

About the Lab

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 cancers.

Cancer Epigenetics

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, metastasis, 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.

Technologies for mapping chromatin and chromosomal structure

We innovate and combine technologies in stem cell biology, biochemistry, imaging, and genome engineering with next-generation sequencing and microscopy to achieve increasingly precise, genome- wide views of chromatin structure and genome topology.

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.

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 now apply emerging chromatin and genome engineering approaches to study how bivalent domains and interacting regulatory elements program gene expression in development and disease.

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.

Selected Publications

Flavahan WA, Drier Y, Johnstone SE, Hemming ML, Tarjan DR, Hegazi E, Shareef SJ, Javed NM, Raut CP, Eschle BK, Gokhale PC, Hornick JL, Sicinska ET, Demetri GD, Bernstein BE. Altered chromosomal topology drives oncogenic programs in SDH-deficient GIST. Nature. 2019; 575:229-33.

van Galen P, Hovestadt V, Wadsworth MH, Hughes TK, Griffin GK, Battaglia S, Verga JA, Stephansky J, Pastika TJ, Lombardi Story J, Pinkus GS, Pozdnyakova O, Galinsky I, Stone RM, Graubert TA, Shalek AK, Aster JC, Lane AA, Bernstein BE. Single-Cell RNA-Seq Reveals AML Hierarchies Relevant to Disease Progression and Immunity. Cell 2019; 176:1265-81.

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.

Flavahan WA, Drier Y, Liau BB, Gillespie SM, Venteicher AS, Stemmer-Rachamimov AO, Suva ML, Bernstein BE. Insulator dysfunc- tion 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.