Nucleosome eviction and activated transcription require p300 acetylation of histone H3 lysine 14
Nucleosome eviction and activated transcription require p300 acetylation of histone H3 lysine 14
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DOI：
10.1073/pnas.1009650107
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发表时间：
2010-11-09
影响因子：
11.1
通讯作者：
Nyborg, Jennifer K.
中科院分区：
文献类型：
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作者：
Luebben, Whitney R.;Sharma, Neelam;Nyborg, Jennifer K.
组蛋白翻译后修饰和染色质动力学与真核基因表达有着密不可分的联系。在已经表征的许多修饰中，组蛋白尾部乙酰化与转录激活最强相关。在后生动物中，转录活性基因的启动子通常没有物理抑制性核小体，与大RNA聚合酶II转录机器的同时结合一致。组蛋白乙酰转移酶p300也被检测到在活跃的基因启动子，侧翼的区域组蛋白超乙酰化。虽然组蛋白尾部乙酰化和基因激活之间的相关性已经明确，但乙酰化促进这一基本生物学过程的机制仍然知之甚少。为了探索乙酰化在核小体动力学中的作用，我们利用了一种固定化的模板，该模板携带有用野生型和突变组蛋白的各种组合重建的天然启动子。我们发现，组蛋白H3的N-末端尾巴是必不可少的激活剂，p300，乙酰辅酶A依赖的核小体驱逐介导的组蛋白伴侣Nap 1。值得注意的是，我们确定H3赖氨酸14作为必要的p300乙酰化底物所需的组蛋白八聚体从启动子DNA的解离。总之，总共11个独特的突变八聚体组证实了这些观察结果，并揭示了核小体驱逐和强激活剂和乙酰辅酶A依赖的转录激活之间的惊人的相关性。这些新的发现揭示了H3赖氨酸14乙酰化的独特作用，促进ATP-独立和转录-独立的拆卸启动子核小体的Nap 1。此外，这些研究直接耦合核小体解体与强大的，激活依赖性转录。
Histone posttranslational modifications and chromatin dynamics are inextricably linked to eukaryotic gene expression. Among the many modifications that have been characterized, histone tail acetylation is most strongly correlated with transcriptional activation. In Metazoa, promoters of transcriptionally active genes are generally devoid of physically repressive nucleosomes, consistent with the contemporaneous binding of the large RNA polymerase II transcription machinery. The histone acetyltransferase p300 is also detected at active gene promoters, flanked by regions of histone hyperacetylation. Although the correlation between histone tail acetylation and gene activation is firmly established, the mechanisms by which acetylation facilitates this fundamental biological process remain poorly understood. To explore the role of acetylation in nucleosome dynamics, we utilized an immobilized template carrying a natural promoter reconstituted with various combinations of wild-type and mutant histones. We find that the histone H3 N-terminal tail is indispensable for activator, p300, and acetyl-CoA- dependent nucleosome eviction mediated by the histone chaperone Nap1. Significantly, we identify H3 lysine 14 as the essential p300 acetylation substrate required for dissociation of the histone octamer from the promoter DNA. Together, a total of 11 unique mutant octamer sets corroborated these observations and revealed a striking correlation between nucleosome eviction and strong activator and acetyl-CoA-dependent transcriptional activation. These novel findings uncover an exclusive role for H3 lysine 14 acetylation in facilitating the ATP-independent and transcription-independent disassembly of promoter nucleosomes by Nap1. Furthermore, these studies directly couple nucleosome disassembly with strong, activator-dependent transcription.