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 in-cell 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.

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，无需基因操作即可在活细胞中引入组蛋白修饰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，它与核小体的酸性贴片结合并促进活细胞中 H2BK120 的区域选择性合成组蛋白乙酰化。催化剂中聚乙二醇的大小是其细胞内代谢稳定性、与组蛋白结合亲和力和高活性的关键决定因素。11 在没有基因操作的情况下促进的合成乙酰化与生理 H2B 泛素化竞争并抑制，这是调节染色质功能的标志，例如转录和 DNA 损伤反应。因此，化学催化剂将成为操纵表观基因组以解开活细胞中的表观遗传机制的有用工具。