Dot1l与Npm1合作,在胚胎干细胞中抑制内源逆转录病毒MERVL
Xin Zhao1, Xiaomin Li1, Haiyang Sun1
1State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, Tianjin 300350, China.
Nucleic acids research
|July 31, 2023
概括
在胚胎干细胞 (ESC) 中,Dot1l 蛋白通过与 Npm1 和基因素 H1.1 相互作用来抑制内源逆转录病毒 (MERVL). 这阻止了2细胞状状态和 trofhectoderm 差异化的激活.
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
- 基因规则 基因规则
背景情况:
- Dot1l 是一种基因组甲基转移酶,已知与活性转录相关的 H3K79 甲基化.
- 然而,Dot1l也在基因沉默中发挥作用,但它的目标和机制仍然不清楚.
- 内源逆转录病毒 (ERV) 涉及基因组稳定性和细胞分化.
研究的目的:
- 研究Dot1l在抑制胚胎干细胞 (ESC) 转录中的作用.
- 阐明Dot1l抑制内源逆转录病毒元素的机制,特别是MERVL.
- 了解Dot1l在维护ESC身份和差异化潜力的非正规功能.
主要方法:
- 在鼠标ESC中删除dot1l.
- 转录组分析 (RNA-seq) 来评估基因表达变化.
- 共同免疫沉和免疫光以研究蛋白质-蛋白质和蛋白质-DNA相互作用.
- 历史素H1和无处不在的测试.
主要成果:
- Dot1l删除激活MERVL表达,并诱导ESC中的2细胞类状态.
- Dot1l 缺陷使ESCs 易于进行 trofhectoderm 差异化.
- Dot1l与Npm1相互作用,并与MERVL基位共定位,这两种蛋白质对于MERVL抑制至关重要.
- Dot1l-Npm1复合体通过控制素H1水平和沉积来调节MERVL,Dot1l促进Npm1与H1的相互作用以抑制H1无处不在.
结论:
- 在ESC中,Dot1l通过一种新的机制抑制MERVL,这是一种关键的内源性逆转录病毒,涉及Npm1和基因素H1的陪伴.
- 这种Dot1l的功能对于抑制二细胞状状态和防止异常分化至关重要.
- 这项研究揭示了Dot1l在维持ESC多能性和基因组完整性方面具有非正规的转录抑制作用.
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