新型组蛋白赖氨酸酰基化修饰调控的基因转录及疾病

Gene Transcription and Disease Mediated by Novel Histone Lysine Acylation

染色质是人类遗传信息的载体,位于染色质上的基因在不同的时空条件下的精准表达调控与DNA的可接触性和染色质相关复合物的密切关联。组蛋白是染色质的重要组成成份,组蛋白上的多种化学修饰,例如乙酰化、甲基化和磷酸化等构成组蛋白密码,实时调控染色质的开放程度及转录调节复合物与染色质的结合,导致基因转录的激活或抑制。随着高分辨率质谱和专一性化学修饰抗体制备技术的提高,一系列新型组蛋白赖氨酸酰基化修饰,例如巴豆酰化、乳酸酰化和琥珀酰化等被发现,进一步扩展了组蛋白密码的多样性,显著增加了组蛋白密码调控基因转录的复杂性。本文着重概述了新近发现的赖氨酸巴豆酰化、乳酸酰化、琥珀酰化、异丁酰化、甲基丙烯酰化和异烟酰化等新型组蛋白赖氨酸酰基化修饰的书写、阅读及擦除的动态调控分子机制,总结了这些组蛋白酰基化修饰在基因表达中的功能及调控机制,阐述了新型组蛋白酰基化修饰与人类疾病的关联,提出新型组蛋白酰基化修饰研究面临的挑战和未来研究的方向。

Chromatin is the carrier of human genetic information,and the transcriptional regulation of genes located on chromatin under different spatial and temporal conditions is closely linked to DNA accessibility and chromatin-associated complexes.Histone chemical modifications like acetylation,methylation,phosphorylation constitute the histone codes which regulate the chromatin accessibility and the association of transcriptional complexes with chromatin,resulting in the activation or repression of gene transcription in real-time.With significant technical enhancement of high-resolution mass spectrometry and the antibody preparation of protein chemical modifications,a series of novel histone acyl-lysine like crotonyl-,lactyl-,succinyl-etc.are identified,significantly expanding the diversity of the histone codes and increasing the complexity of histone code mediated gene transcription.In this review,we overview the dynamic regulation of crotonyl-lysine,lactyl-lysine,succinyl-lysine,isobutyryl-lysine,methacryl-lysine,and isonicotinyl-lysine of histone through the writers,erasers and readers,and further highlight our current understanding about gene transcription mediated by these novel types of histone lysine acylation in various biological content as well as human diseases linked to histone lysine acylation.Finally,the challenge and future prospective of lysine acylation in biology are further outlined.