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A Rapid In Vivo Bioassay for Developmentally Active Enhancers

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通过ERK的直接增强器调节来驱动动力学系原始化

William B Hamilton¹, Yaron Mosesson², Rita S Monteiro¹

¹The Novo Nordisk Foundation Center for Stem Cell Biology, Copenhagen, Denmark.

|November 8, 2019

概括

纤维细胞生长因子 - 细胞外信号调节激酶 (FGF-ERK) 信号通过调节增强剂活性可逆控制胚胎干细胞中的基因转录. 这种可塑性使细胞保持多能性,直到持续的信号引发不可逆转的分化.

科学领域:

细胞生物学
发育生物学
分子生物学

背景情况:

细胞状态的转变是多细胞生物的发展的基础.
纤维细胞生长因子 - 细胞外信号调节激酶 (FGF-ERK) 信号影响胚胎干细胞 (ES细胞) 的分化和自我更新.
ERK信号可以诱导细胞群中的可逆异质性,允许细胞在多能和分化状态之间过渡.

研究的目的:

研究ERK信号调节ES细胞转录的分子机制.
确定ERK信号如何影响增强剂活性和基因表达.
了解转录因子结合和调解成分在ERK依赖的转录调节和细胞命运承诺中的作用.

主要方法:

分析小鼠胚胎干细胞中的基因转录和增强剂活性.
对基因和增强剂的RNA聚合酶II和辅因子动态的研究.
评估MED24中介组件在ERK信号通路中的作用.
在不同的ERK信号条件下检查多能转录因子结合动态.

主要成果:

通过直接影响增强剂活性,独立于转录因子结合变化,ERK信号可逆调节ES细胞的转录.
在基因和增强剂中,ERK信号控制着RNA聚合酶II和辅助因子的动态关联和解离,MED24发挥着关键作用.
多能性因子的持续结合保持了基因的可再生性,从而保持了细胞的可塑性.
持续的ERK信号导致多能性因子水平降低,不可逆转的基因沉默和细胞命运承诺.

结论:

作为ES细胞转录可塑性的关键调节者,它平衡自我更新和分化.
信号通路,转录因子和媒介复合体之间的动态相互作用决定了细胞命运.
维持多能因子占用对于细胞对短暂信号的反应至关重要,而持续的信号驱动不可逆转的承诺.

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