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      HDAC inhibition results in widespread alteration of the histone acetylation landscape and BRD4 targeting to gene bodies

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          SUMMARY

          Histone acetylation levels are regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs) that antagonistically control the overall balance of this post-translational modification. HDAC inhibitors (HDACi) are potent agents that disrupt this balance and are used clinically to treat diseases including cancer. Despite their use, little is known about their effects on chromatin regulators, particularly those that signal through lysine acetylation. We apply quantitative genomic and proteomic approaches to demonstrate that HDACi robustly increases a low-abundance histone 4 polyacetylation state, which serves as a preferred binding substrate for several bromodomain-containing proteins, including BRD4. Increased H4 polyacetylation occurs in transcribed genes and correlates with the targeting of BRD4. Collectively, these results suggest that HDAC inhibition functions, at least in part, through expansion of a rare histone acetylation state, which then retargets lysine-acetyl readers associated with changes in gene expression, partially mimicking the effect of bromodomain inhibition.

          In Brief

          Slaughter et al. use proteomic and genomic approaches to quantitatively assess the impact of histone deacetylase inhibitor (HDACi) treatment on histone acetylation and BRD4 binding genome-wide. Their studies show that HDACi treatment causes histone polyacetylation and recruitment of BRD4, particularly in the gene bodies of actively transcribed genes.

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          Author and article information

          Journal
          101573691
          39703
          Cell Rep
          Cell Rep
          Cell reports
          2211-1247
          8 February 2021
          19 January 2021
          16 February 2021
          : 34
          : 3
          : 108638
          Affiliations
          [1 ]Department of Genetics, Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC 27599, USA
          [2 ]Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
          [3 ]Department of Biological and Environmental Sciences, Longwood University, Farmville, VA 23909, USA
          [4 ]Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA
          [5 ]Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
          [6 ]Geriatric Research, Education, and Clinical Center, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA
          [7 ]Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA
          [8 ]Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA
          [9 ]Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA
          [10 ]Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA
          [11 ]Department of Pediatrics, University of North Carolina, Chapel Hill, NC 27514, USA
          [12 ]These authors contributed equally
          [13 ]Lead Contact
          Author notes

          AUTHOR CONTRIBUTIONS

          B.D.S., I.J.D., and S.B.R. conceived the study. E.K.S. performed ChIP-seq experiments. and A.K. performed RNA-seq experiments and chromatin fractionations. M.J.S. analyzed ChIP-seq and RNA-seq data. K.F.C., T.H., and L.D.B. generated bromodomains used for the peptide arrays. C.D.A., B.A.G., and S.Z.J. performed mass spectrometry experiments. S.B.R. and E.K.S. performed bromodomain microarrays. M.J.S., E.K.S., I.J.D., and B.D.S. wrote and edited the manuscript.

          Article
          PMC7886050 PMC7886050 7886050 nihpa1664956
          10.1016/j.celrep.2020.108638
          7886050
          33472068
          4590c411-3e0b-4b91-bc77-de93799747ef
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