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组蛋白 H3 赖氨酸 14 乙酰化在染色质中赋予了对表观遗传沉默复合物的去乙酰化酶和去甲基化酶活性的抗性。

Lysine-14 acetylation of histone H3 in chromatin confers resistance to the deacetylase and demethylase activities of an epigenetic silencing complex.

机构信息

Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, United States.

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States.

出版信息

Elife. 2018 Jun 5;7:e37231. doi: 10.7554/eLife.37231.

DOI:10.7554/eLife.37231
PMID:29869982
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6019071/
Abstract

The core CoREST complex (LHC) contains histone deacetylase HDAC1 and histone demethylase LSD1 held together by the scaffold protein CoREST. Here, we analyze the purified LHC with modified peptide and reconstituted semisynthetic mononucleosome substrates. LHC demethylase activity toward methyl-Lys4 in histone H3 is strongly inhibited by H3 Lys14 acetylation, and this appears to be an intrinsic property of the LSD1 subunit. Moreover, the deacetylase selectivity of LHC unexpectedly shows a marked preference for H3 acetyl-Lys9 versus acetyl-Lys14 in nucleosome substrates but this selectivity is lost with isolated acetyl-Lys H3 protein. This diminished activity of LHC to Lys-14 deacetylation in nucleosomes is not merely due to steric accessibility based on the pattern of sensitivity of the LHC enzymatic complex to hydroxamic acid-mediated inhibition. Overall, these studies have revealed how a single Lys modification can confer a composite of resistance in chromatin to a key epigenetic enzyme complex involved in gene silencing.

摘要

核心 CoREST 复合物（LHC）包含组蛋白去乙酰化酶 HDAC1 和组蛋白去甲基化酶 LSD1，由支架蛋白 CoREST 连接在一起。在这里，我们使用修饰肽和重新构建的半合成单核小体底物来分析纯化的 LHC。LHC 对组蛋白 H3 中甲基化-Lys4 的去甲基酶活性强烈受到 H3 Lys14 乙酰化的抑制，而这似乎是 LSD1 亚基的固有特性。此外，LHC 的去乙酰化选择性出人意料地对核小体底物中的 H3 乙酰-Lys9 表现出明显的偏好，而不是乙酰-Lys14，但这种选择性在分离的乙酰化-Lys H3 蛋白中丧失。这种 LHC 对核小体中 Lys-14 去乙酰化的活性降低不仅仅是由于基于 LHC 酶复合物对羟肟酸介导抑制的敏感性模式的空间位阻所致。总的来说，这些研究揭示了单个赖氨酸修饰如何赋予参与基因沉默的关键表观遗传酶复合物对染色质的复合抗性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f38f/6019071/1a3d77899b59/elife-37231-fig8.jpg
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