Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory of Molecular Recognition and Function, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
Adv Sci (Weinh). 2024 Nov;11(41):e2404608. doi: 10.1002/advs.202404608. Epub 2024 Sep 9.
Post-translational modifications on the histone H3 tail regulate chromatin structure, impact epigenetics, and hence the gene expressions. Current chemical modulation tools, such as unnatural amino acid incorporation, protein splicing, and sortase-based editing, have allowed for the modification of histones with various PTMs in cellular contexts, but are not applicable for editing native chromatin. The use of small organic molecules to manipulate histone-modifying enzymes alters endogenous histone PTMs but lacks precise temporal and spatial control. To date, there has been no achievement in modulating histone methylation in living cells with spatiotemporal resolution. In this study, a new method is presented for temporally manipulating histone dimethylation H3K9me2 using a photo-responsive inhibitor that specifically targets the methyltransferase G9a on demand. The photo-caged molecule is stable under physiological conditions and cellular environments, but rapidly activated upon exposure to light, releasing the bioactive component that can immediately inhibit the catalytic ability of the G9a in vitro. Besides, this masked compound could also efficiently reactivate the inhibition of methyltransferase activity in living cells, subsequently suppress H3K9me2, a mark that regulates various chromatin functions. Therefore, the chemical system will be a valuable tool for manipulating the epigenome for therapeutic purposes and furthering the understanding of epigenetic mechanisms.
组蛋白 H3 尾部的翻译后修饰调节染色质结构，影响表观遗传学，从而影响基因表达。目前的化学调节工具，如非天然氨基酸掺入、蛋白质剪接和基于 sortase 的编辑，已经允许在细胞环境中用各种 PTM 修饰组蛋白，但不适用于编辑天然染色质。使用小分子有机化合物来操纵组蛋白修饰酶可以改变内源性组蛋白 PTM，但缺乏精确的时空控制。迄今为止，还没有实现利用时空分辨率调节活细胞中的组蛋白甲基化。在这项研究中，提出了一种新的方法，使用光响应抑制剂来暂时操纵组蛋白二甲基化 H3K9me2，该抑制剂特异性地按需靶向甲基转移酶 G9a。光笼分子在生理条件和细胞环境下稳定，但在暴露于光下时迅速激活，释放出生物活性成分，可立即抑制 G9a 的体外催化能力。此外，这种掩蔽化合物还可以有效地重新激活活细胞中转录酶活性的抑制，从而抑制 H3K9me2，这是一种调节各种染色质功能的标记。因此，该化学系统将是一种用于治疗目的操纵表观基因组和深入了解表观遗传机制的有价值的工具。
