在响应PROTAC诱导的ASH2L降解时,组织蛋白标记,染色质可访问性和基因表达的顺序放松
Mirna Barsoum1, Roksaneh Sayadi-Boroujeni2,3, Alexander T Stenzel2,4
1Institute of Biochemistry and Molecular Biology, Faculty of Medicine, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany. mirna.barsoum@rwth-aachen.de.
Scientific reports
|December 19, 2023
概括
使用PROTACs快速降解ASH2L蛋白揭示了它在细胞增殖中的直接作用. ASH2L的损失会影响基因组甲基化模式和基因转录,但下游效应会显著延迟.
科学领域:
- 表观遗传学和基因调控
- 分子生物学分子生物学
- 发展生物学 发展生物学
背景情况:
- ASH2L是COMPASS/KMT2复合体的关键组成部分,对于基因素H3氨酸4 (H3K4) 甲基化至关重要.
- H3K4甲基化标志着活性调节元素,但其确切的功能意义仍然不完全理解.
- 由于ASH2L的半衰期很长,因此对其直接的发育和细胞后果的研究变得复杂.
研究的目的:
- 研究ASH2L损失对细胞过程和表观遗传标记的直接功能影响.
- 通过使用向蛋白质降解方法来克服ASH2L长半衰期所带来的局限性.
主要方法:
- 采用了一种蛋白解-向金氏体 (PROTAC) 系统,以快速和有针对性地降解ASH2L蛋白.
- 在ASH2L枯竭后分析了小鼠胚胎纤维细胞的增殖.
- 评估了基因素修饰 (H3K4me3,H3K4me1,H3K27ac,H3K27me3) 和染色质结构的变化.
- 监测新生和整体RNA表达水平.
主要成果:
- 快速的ASH2L降解抑制了小鼠胚胎纤维细胞的增殖.
- 在ASH2L损失后不久,H3K4me3水平下降,促进者之间有不同的半衰期.
- H3K4me1水平显示出动态变化,在促进剂增加,在某些增强剂减少.
- 基因组标记H3K27ac和H3K27me3,以及染色质紧缩,受到显著延迟的影响.
- 虽然新生的转录在早期没有受到影响,但整体RNA表达后来被放松了.
结论:
- ASH2L对于维持细胞增殖和调节特定的质子甲基化模式至关重要.
- 尽管蛋白质降解速度很快,但ASH2L损失的下游细胞和转录效应是有序的,并且以显著的延迟发生.
- 基因转录调节系统看起来强大且缓冲,在失去关键表观遗传调节器 (如ASH2L) 之后,需要大量时间才能出现重大干扰.
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