小柯机器人

丹麦诺和诺德基金会干细胞生物学中心Joshua M. Brickman小组发现，动态细胞谱系启动是由ERK通过直接增强子调节来驱动的。该研究于2019年11月6日在线发表于国际一流学术期刊《自然》。

研究人员发现细胞外信号调节激酶（ERK）通过直接影响增强子的活性而无需改变转录因子的结合，从而可逆地调节胚胎干细胞（ES细胞）中的转录。ERK触发RNA聚合酶II和相关辅因子与基因和增强子之间可逆的结合和解离，而中介体组分MED24在ERK依赖性转录调节中起重要作用。尽管中介体成分的结合直接响应信号，但是多能性因子与诱导和抑制基因的持久结合将它们标记为响应ERK活性波动而被激活和/或重新激活。

在被抑制的基因中，多潜能网络的几个核心成分起着驱动其自身表达并维持ES细胞状态的作用。如果它们的结合丢失，则重新激活转录的能力将受到损害。因此，只要维持转录因子的占位，可塑性就保持不变，使细胞能够区分瞬时信号和持续信号。如果ERK信号持续存在，则多能性转录因子水平会因蛋白质更新而降低，并且可能发生不可逆的基因沉默和改变。

据介绍，了解多细胞生物中细胞行为的核心问题是，细胞如何退出一种转录状态并被采纳并最终致力于另一种转录状态。成纤维细胞生长因子-细胞外信号调节激酶（FGF-ERK）信号驱动小鼠ES细胞和着床前胚胎向原始内胚层的分化，抑制ERK支持ES细胞自我更新。旁分泌FGF-ERK信号传导诱导异质性，从而使细胞从多能性可逆地发展为原始内胚层，同时保留其重新进入自我更新的能力。

附：英文原文

Title: Dynamic lineage priming is driven via direct enhancer regulation by ERK

Author: William B. Hamilton, Yaron Mosesson, Rita S. Monteiro, Kristina B. Emdal, Teresa E. Knudsen, Chiara Francavilla, Naama Barkai, Jesper V. Olsen, Joshua M. Brickman

Issue&Volume: 2019-11-06

Abstract: Central to understanding cellular behaviour in multi-cellular organisms is the question of how a cell exits one transcriptional state to adopt and eventually become committed to another. Fibroblast growth factor-extracellular signal-regulated kinase (FGF -ERK) signalling drives differentiation of mouse embryonic stem cells (ES cells) and pre-implantation embryos towards primitive endoderm, and inhibiting ERK supports ES cell self-renewal1. Paracrine FGFERK signalling induces heterogeneity, whereby cells reversibly progress from pluripotency towards primitive endoderm while retaining their capacity to re-enter self-renewal2. Here we find that ERK reversibly regulates transcription in ES cells by directly affecting enhancer activity without requiring a change in transcription factor binding. ERK triggers the reversible association and disassociation of RNA polymerase II and associated co-factors from genes and enhancers with the mediator component MED24 having an essential role in ERK-dependent transcriptional regulation. Though the binding of mediator components responds directly to signalling, the persistent binding of pluripotency factors to both induced and repressed genes marks them for activation and/or reactivation in response to fluctuations in ERK activity. Among the repressed genes are several core components of the pluripotency network that act to drive their own expression and maintain the ES cell state; if their binding is lost, the ability to reactivate transcription is compromised. Thus, as long as transcription factor occupancy is maintained, so is plasticity, enabling cells to distinguish between transient and sustained signals. If ERK signalling persists, pluripotency transcription factor levels are reduced by protein turnover and irreversible gene silencing and commitment can occur. ERK reversibly regulates embryonic stem cell transcription via selective redistribution of co-factors and RNA polymerase from pluripotency to early differentiation enhancers, while leaving transcription factors bound to their enhancers, thus preserving plasticity.

DOI: 10.1038/s41586-019-1732-z

Source:https://www.nature.com/articles/s41586-019-1732-z

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