DOT1L是在重编程到多能性的过程中阻碍了组织素乙化
Coral K Wille1, Xiaoya Zhang1,2, Spencer A Haws1,3
1Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA.
Science advances
|November 17, 2023
概括
在体细胞中抑制DOT1L可以通过改变组质子修饰和促进超转录来增强对诱导多能干细胞的重编程,模仿胚胎干细胞的特性.
科学领域:
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
- 干细胞生物学 干细胞生物学
- 分子生物学分子生物学
背景情况:
- 胚胎干细胞 (ESC) 具有转录允许的染色质,通常由基因激活基因组蛋白修饰标记.
- 一个值得注意的例外是DOT1L介导的H3K79二甲基化 (H3K79me2),通常被视为转录促进剂.
- 与体细胞相比,ESCs在家政基因中显示了H3K79me2的降低,尽管新生的转录率更高,但转录开始地点 (TSS) 的RNA聚合酶II (RNAPII) 较低.
研究的目的:
- 研究DOT1L和H3K79me2在细胞重编程和多能性的作用.
- 为了确定DOT1L抑制对体细胞重编程期间的基因素修饰和RNAPII动态的影响.
主要方法:
- 在ESC和体细胞中对H3K79me2和RNAPII占用率的比较分析.
- 在体细胞中药理上抑制DOT1L.
- 评估DOT1L抑制后的重编程效率和基因素修饰变化 (H3K27甲基化,基因素乙化).
主要成果:
- DOT1L抑制显著提高了体细胞重编程成诱导多能干细胞的效率.
- 抑制导致TSS的ESC类RNAPII模式,并补偿强制性RNAPII暂停.
- DOT1L抑制提高了H3K27甲基化和基因素乙化,这对于增强重编程至关重要,特别是在H3K79me2贫乏的位置.
结论:
- DOT1L 抑制促进过乙化和超转录,使重新编程的细胞具有多能性质.
- 针对DOT1L提供了一种改善诱导多能干细胞生成的潜在策略.
- 这些发现凸显了H3K79me2在调节多能性和重编程方面的复杂作用.
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