Biomimetic Artificial Epigenetic Code for Targeted Acetylation of Histones
Biomimetic Artificial Epigenetic Code for Targeted Acetylation of Histones
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用于组蛋白靶向乙酰化的仿生人工表观遗传密码
DOI：
10.1021/jacs.8b01518
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
H.
中科院分区：
文献类型：
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作者：
Taniguchi;J.; Feng;Y.; Pandian;G.; Hashiya;F.; Hidaka;T.; Hashiya;K.; Park;S.; Bando;T.; Ito;S.; Sugiyama;H.
虽然基因座特异性乙酰化组蛋白在真核基因表达中的核心作用已经确立，但用于调节特定核小体位点乙酰化的设计工具的可用性仍然有限。在这里，我们开发了一种独特的策略，通过构建一个双功能分子命名为Bi-PIP引入乙酰化。Bi-PIP具有作为P300/CBP募集剂的P300/CBP选择性溴结构域抑制剂（Bi）和作为序列选择性DNA结合剂的吡咯-咪唑聚酰胺（PIP）。生物化学分析证实，Bi-PIP将P300募集到具有其靶DNA序列的核小体中，并广泛加速乙酰化。Bi-PIP还激活活细胞内具有相应同源DNA序列的基因的转录。我们的研究结果表明，Bi-PIP可以作为一个合成的可编程组蛋白乙酰化的代码，它模拟了溴结构域介导的组蛋白乙酰化的自然繁殖系统，以序列选择性的方式激活基因表达。
While the central role of locus-specific acetylation of histone proteins in eukaryotic gene expression is well established, the availability of designer tools to regulate acetylation at particular nucleosome sites remains limited. Here, we develop a unique strategy to introduce acetylation by constructing a bifunctional molecule designated Bi-PIP. Bi-PIP has a P300/CBP-selective bromodomain inhibitor (Bi) as a P300/CBP recruiter and a pyrrole–imidazole polyamide (PIP) as a sequence-selective DNA binder. Biochemical assays verified that Bi-PIPs recruit P300 to the nucleosomes having their target DNA sequences and extensively accelerate acetylation. Bi-PIPs also activated transcription of genes that have corresponding cognate DNA sequences inside living cells. Our results demonstrate that Bi-PIPs could act as a synthetic programmable histone code of acetylation, which emulates the bromodomain-mediated natural propagation system of histone acetylation to activate gene expression in a sequence-selective manner.