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

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HDAC inhibition results in widespread alteration of the histone acetylation landscape and BRD4 targeting to gene bodies
Cell Reports ( IF 8.8 ) Pub Date : 2021-01-19 , DOI: 10.1016/j.celrep.2020.108638
Mariesa J Slaughter ₁ , Erin K Shanle ₂ , Abid Khan ₃ , Katrin F Chua ₄ , Tao Hong ₅ , Lisa D Boxer ₅ , C David Allis ₆ , Steven Z Josefowicz ₇ , Benjamin A Garcia ₈ , Scott B Rothbart ₉ , Brian D Strahl ₁₀ , Ian J Davis ₁₁

Affiliation

Department of Genetics, Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Department of Biological and Environmental Sciences, Longwood University, Farmville, VA 23909, USA.
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA.
Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Geriatric Research, Education, and Clinical Center, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA.
Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA.
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA.
Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
Department of Genetics, Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA.
Department of Genetics, Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Pediatrics, University of North Carolina, Chapel Hill, NC 27514, USA.

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.

中文翻译：

HDAC 抑制导致组蛋白乙酰化景观和 BRD4 靶向基因体的广泛改变

组蛋白乙酰化水平由组蛋白乙酰转移酶 (HAT) 和组蛋白去乙酰化酶 (HDAC) 调节，它们拮抗地控制这种翻译后修饰的整体平衡。HDAC 抑制剂 (HDACi) 是破坏这种平衡的有效药物，临床上用于治疗包括癌症在内的疾病。尽管使用了它们，但人们对它们对染色质调节剂的影响知之甚少，尤其是那些通过赖氨酸乙酰化发出信号的调节剂。我们应用定量基因组和蛋白质组学方法来证明 HDACi 有力地增加了低丰度组蛋白 4 多乙酰化状态，该状态可作为包括 BRD4 在内的几种含溴结构域蛋白的首选结合底物。H4 多乙酰化增加发生在转录基因中，并与 BRD4 的靶向相关。集体，

更新日期：2021-01-19

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