<br>组蛋白H3K18和H3K23乙酰化指导建立MLL介导的H3K4甲基化,Journal of Biological Chemistry

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组蛋白H3K18和H3K23乙酰化指导建立MLL介导的H3K4甲基化
Journal of Biological Chemistry ( IF 4.0 ) Pub Date : 2024-07-01 , DOI: 10.1016/j.jbc.2024.107527
Geoffrey C Fox ₁ , Karl F Poncha ₂ , B Rutledge Smith ₃ , Lara N van der Maas ₃ , Nathaniel N Robbins ₄ , Bria Graham ₄ , Jill M Dowen ₅ , Brian D Strahl ₆ , Nicolas L Young ₂ , Kanishk Jain ₇

Affiliation

Curriculum in Genetics and Molecular Biology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas, USA.
Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
EpiCypher, Inc, Durham, North Carolina, USA.
Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Integrative Program for Biological and Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Curriculum in Genetics and Molecular Biology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

在未修饰的状态下，带正电荷的组蛋白 N 末端尾部与核小体 DNA 结合，这不仅限制了对潜在 DNA 的访问，而且限制了对受结合和/或修饰的关键尾残基的访问。电荷中和修饰，例如组蛋白乙酰化，用于破坏这种 DNA-尾相互作用，从而促进此类残基的获取。我们之前表明，多乙酰化介导的染色质“开关”通过 MLL1 甲基转移酶复合物控制 H3K4me3 的读写能力。在这里，我们辨别了沿 H3 尾部的位点特异性乙酰化态的相对贡献，并将我们的询问扩展到其他染色质修饰物。我们表明 H3 尾乙酰化对 MLL1 的 H3K4 甲基化的贡献是高度可变的，H3K18 和 H3K23 乙酰化表现出强大的刺激作用，并且这延伸到相关的 H3K4 甲基转移酶复合物 MLL4。我们表明，H3K4me1 和 H3K4me3 优先与带有双重 H3K18 和 H3K23 乙酰化（H3{K18acK23ac}）的 H3 N 末端尾部蛋白质形式共富集。我们进一步表明，这种效应对H3K4甲基化是特异性的，而针对其他H3尾残基（H3K9，H3K27和H3K36）的甲基转移酶，针对核小体核心的甲基转移酶（H3K79）和针对直接邻接H3K4的残基的激酶（H3T3）对尾乙酰化不敏感。总之，这些发现表明 H3K18 和 H3K23 乙酰化对 H3K4 甲基化的独特而强大的刺激，并为为什么在活性基因表达的背景下 H3K4 甲基化通常与组蛋白乙酰化相关提供了关键见解。

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Histone H3K18 & H3K23 acetylation directs establishment of MLL-mediated H3K4 methylation

In an unmodified state, positively charged histone N-terminal tails engage nucleosomal DNA in a manner which restricts access to not only the underlying DNA but also key tail residues subject to binding and/or modification. Charge-neutralizing modifications, such as histone acetylation, serve to disrupt this DNA–tail interaction, facilitating access to such residues. We previously showed that a polyacetylation-mediated chromatin “switch” governs the read-write capability of H3K4me3 by the MLL1 methyltransferase complex. Here, we discern the relative contributions of site-specific acetylation states along the H3 tail and extend our interrogation to other chromatin modifiers. We show that the contributions of H3 tail acetylation to H3K4 methylation by MLL1 are highly variable, with H3K18 and H3K23 acetylation exhibiting robust stimulatory effects and that this extends to the related H3K4 methyltransferase complex, MLL4. We show that H3K4me1 and H3K4me3 are found preferentially co-enriched with H3 N-terminal tail proteoforms bearing dual H3K18 and H3K23 acetylation (H3{K18acK23ac}). We further show that this effect is specific to H3K4 methylation, while methyltransferases targeting other H3 tail residues (H3K9, H3K27, & H3K36), a methyltransferase targeting the nucleosome core (H3K79), and a kinase targeting a residue directly adjacent to H3K4 (H3T3) are insensitive to tail acetylation. Together, these findings indicate a unique and robust stimulation of H3K4 methylation by H3K18 and H3K23 acetylation and provide key insight into why H3K4 methylation is often associated with histone acetylation in the context of active gene expression.

更新日期：2024-07-01

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