通过PARP-DUX4调控轴向功能人类全能干细胞状态进行蛋白基因组重编程
bioRxiv : the preprint server for biology
|June 25, 2024
概括
人类多能干细胞通过抑制PARP1和Tankyrases被重新编程成全能干细胞. 这些细胞有助于所有胚胎和胚胎外的基因系,为早期人类发育提供了一个模型.
科学领域:
- 发展生物学 发展生物学
- 干细胞生物学 干细胞生物学
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
背景情况:
- 多ADP-ribose聚合酶 (PARP),包括PARP1和Tankyrases (TNKS1/2),在胚胎早期发育期间调节基因组和蛋白质组.
- 人类多能干细胞 (hPSCs) 是研究全能性和早期人类胚胎发生的一个关键模型.
研究的目的:
- 为了研究hPSCs的表观遗传重编程成全能类细胞.
- 探索PARP1和TNKS抑制在实现全能性的作用.
- 描述重新编程细胞的发育潜力和分子特征.
主要方法:
- 使用PARP1和TNKS抑制剂的hPSCs的化学原始逆转.
- 重编程细胞 (TIRN细胞) 的单细胞RNA测序和蛋白质组分析.
- 使用ChIP测序 (ChIP-Seq) 来绘制转录因子结合部位的地图.
- 通过将TIRN细胞注射到小鼠胚胎中,形成物种间的奇梅拉.
主要成果:
- 在PARP1/TNKS抑制下,hPSCs在表观遗传学上被重新编程为克隆芽细胞样干细胞 (TIRN细胞).
- TIRN细胞表达了多个早期胚胎阶段特征的基因和因素 (4C-8C,原始内皮, trofhectoderm,表皮质).
- 在人-小鼠仿真体中,TIRN细胞对胚胎和非胚胎血统都表现出类似于 totipotent 的贡献.
- 观察到全球ADP-ribosylation关闭和改变的泛化,影响了PARP1/TNKS基质水平和基因表达.
结论:
- 翻译后修改的全球性干扰,特别是ADP-ribosylation和ubiquitination,可以推动表观遗传重编程到人类的全能性.
- PARP1和DUX4与核心多能性因子 (NSO) 合作,调节表观遗传可塑性和发育基因表达.
- 全能TIRN干细胞为研究人类芽细胞体发育提供了一种新型模型,并可能有助于在跨物种喜梅拉中产生人类器官.
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