Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
Cell Biology Center, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama 226-8503, Japan.
Proc Natl Acad Sci U S A. 2021 Jan 26;118(4). doi: 10.1073/pnas.2019554118.
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发挥着关键作用。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，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，它与核小体的酸性斑结合，并在活细胞中促进 H2BK120 处的选择性、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 号催化剂促进的合成乙酰化作用与生理 H2B 泛素化竞争，并抑制调节染色质功能（如转录和 DNA 损伤反应）的标记。因此，这种化学催化剂将是一种有用的工具，可以用于操纵表观基因组，以揭示活细胞中的表观遗传机制。
