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Chromatin regulatory mechanisms and therapeutic opportunities in cancer

Nature Cell Biology volume 21, pages 152–161 (2019)Cite this article

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Abstract

Research over the past several decades has unmasked a major contribution of disrupted chromatin regulatory processes to human disease, particularly cancer. Advances in genome-wide technologies have highlighted frequent mutations in genes encoding chromatin-associated proteins, identified unexpected synthetic lethal opportunities and enabled increasingly comprehensive structural and functional dissection. Here, we review recent progress in our understanding of oncogenic mechanisms at each level of chromatin organization and regulation, and discuss new strategies towards therapeutic intervention.

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Fig. 1: Chromatin regulatory processes in mammalian cells.
Fig. 2: DNMT and TET enzymes and related perturbations in AML.
Fig. 3: Histone H3 methylation modifications and disruption in cancer.
Fig. 4: CRCs in cancer: a focus on mSWI/SNF (BAF) complexes.

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Acknowledgements

We thank members of the Kadoch Laboratory for helpful discussions during preparation of this Review, and Andrew R. D’Avino for computational analysis presented in Fig. 4c. A.M.V. is supported by the Howard Hughes Medical Institute Gilliam Fellowship Program, NIH 5 T32 GM095450-04, and the Ford Foundation Fellowship. C.K. is supported by awards from the NIH DP2 New Innovator Award 1DP2CA195762-01, the American Cancer Society Research Scholar Award RSG-14-051-01-DMC, the Pew-Stewart Scholars in Cancer Research Grant and the Alex’s Lemonade Stand Foundation ‘A’ Award. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or the National Institutes of Health.

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Authors and Affiliations

  1. Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

    Alfredo M. Valencia & Cigall Kadoch

  2. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Alfredo M. Valencia & Cigall Kadoch

  3. Chemical Biology Program, Harvard University, Cambridge, MA, USA

    Alfredo M. Valencia

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A.M.V. and C.K. conceived of the content presented in this Review. A.M.V. and C.K. wrote the manuscript.

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Correspondence to Cigall Kadoch.

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C.K. is a Scientific Founder, Board of Directors member, Scientific Advisory Board member, shareholder and consultant of Foghorn Therapeutics, Inc. (Cambridge, MA, USA).

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Valencia, A.M., Kadoch, C. Chromatin regulatory mechanisms and therapeutic opportunities in cancer. Nat Cell Biol 21, 152–161 (2019). https://doi.org/10.1038/s41556-018-0258-1

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