Early butyrate induced acetylation of histone H4 is proteoform specific and linked to methylation state
Early butyrate induced acetylation of histone H4 is proteoform specific and linked to methylation state
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DOI：
10.1080/15592294.2018.1475979
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发表时间：
2018-05
期刊：
影响因子：
3.7
通讯作者：
Tao Wang;Matthew V. Holt;N. L. Young
中科院分区：
文献类型：
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作者：
Tao Wang;Matthew V. Holt;N. L. Young
摘要组蛋白翻译后修饰（PTM）有助于调节DNA模板过程;然而，相对较少的工作无偏见地探索组蛋白翻译后修饰的单分子组合、其在短时间尺度上的动态变化，或者这些预先存在的组蛋白翻译后修饰如何调节进一步的组蛋白修饰酶活性。我们使用定量自上而下的蛋白质组学无偏地测量组蛋白H4蛋白质型（PTM的单分子组合）丁酸治疗。我们的研究结果表明，组蛋白的蛋白形式的变化在细胞内的丁酸钠的应用程序在10分钟。去除丁酸盐后30分钟内细胞从处理中恢复。令人惊讶的是，含有K20 me 2的蛋白形式是丁酸盐处理后组蛋白乙酰转移酶的几乎唯一的底物。进行性PTM的单分子层次结构主要决定组蛋白PTM的添加和去除（K16 ac> K12 ac ≥ K8 ac> K5 ac，恢复时则相反）。这揭示了潜在的单分子机制，解释了以前报道的，但模糊和无法解释的H4乙酰化模式。因此，预先存在的组蛋白PTM强烈调节组蛋白修饰酶活性，这表明蛋白质形式约束的反应途径是使细胞表观遗传状态长期稳定的关键机制。
ABSTRACT Histone posttranslational modifications (PTMs) help regulate DNA templated processes; however, relatively little work has unbiasedly explored the single-molecule combinations of histone PTMs, their dynamics on short timescales, or how these preexisting histone PTMs modulate further histone modifying enzyme activity. We use quantitative top down proteomics to unbiasedly measure histone H4 proteoforms (single-molecule combinations of PTMs) upon butyrate treatment. Our results show that histone proteoforms change in cells within 10 minutes of application of sodium butyrate. Cells recover from treatment within 30 minutes after removal of butyrate. Surprisingly, K20me2 containing proteoforms are the near-exclusive substrate of histone acetyltransferases upon butyrate treatment. Single-molecule hierarchies of progressive PTMs mostly dictate the addition and removal of histone PTMs (K16ac > K12ac ≥ K8ac > K5ac, and the reverse on recovery). This reveals the underlying single-molecule mechanism that explains the previously reported but indistinct and unexplained patterns of H4 acetylation. Thus, preexisting histone PTMs strongly modulate histone modifying enzyme activity and this suggests that proteoform constrained reaction pathways are crucial mechanisms that enable the long-term stability of the cellular epigenetic state.