Live-cell epigenome manipulation by synthetic histone acetylation catalyst system
Live-cell epigenome manipulation by synthetic histone acetylation catalyst system
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DOI：
10.1073/pnas.2019554118
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发表时间：
2021-01-26
影响因子：
11.1
通讯作者：
Kanai, Motomu
中科院分区：
文献类型：
--
作者：
Fujiwara, Yusuke;Yamanashi, Yuki;Kanai, Motomu
组蛋白的化学修饰，如赖氨酸乙酰化和泛素化，在基因表达的表观遗传调控中起着关键作用。因此，改变表观基因组的方法有望成为阐明表观遗传机制的工具和治疗方法。然而，在没有遗传操作的情况下将组蛋白修饰引入活细胞的完全化学方法是前所未有的。在这里，我们开发了一种化学催化剂PEG-LANA-DSSMe 11，它与核小体的酸性补丁结合，并促进活细胞中H2 BK 120的区域选择性合成组蛋白乙酰化。聚乙二醇在催化剂中的大小是其因斯的关键决定因素。l代谢稳定性、与组蛋白的结合亲和力和高活性。在没有遗传操作的情况下，11促进的合成乙酰化与生理H2 B泛素化竞争并抑制生理H2 B泛素化，这是一种调节染色质功能的标记，如转录和DNA损伤反应。因此，化学催化剂将是一个有用的工具来操纵表观基因组，以解开活细胞中的表观遗传机制。
Chemical modifications of histones, such as lysine acetylation and ubiquitination, play pivotal roles in epigenetic regulation of gene expression. Methods to alter the epigenome thus hold promise as tools for elucidating epigenetic mechanisms and as therapeutics. However, an entirely chemical method to introduce histone modifications in living cells without genetic manipulation is unprecedented. Here, we developed a chemical catalyst, PEG-LANA-DSSMe 11, that binds with nucleosome's acidic patch and promotes regioselective, synthetic histone acetylation at H2BK120 in living cells. The size of polyethylene glycol in the catalyst was a critical determinant for its ince!l metabolic stability, binding affinity to histones, and high activity. The synthetic acetylation promoted by 11 without genetic manipulation competed with and suppressed physiological H2B ubiquitination, a mark regulating chromatin functions, such as transcription and DNA damage response. Thus, the chemical catalyst will be a useful tool to manipulate epigenome for unraveling epigenetic mechanisms in living cells.