研究揭示ERK激酶調控細胞譜系變化的機制
作者：
小柯機器人發布時間：2019/11/7 14:09:16
丹麥諾和諾德基金會幹細胞生物學中心Joshua M. Brickman小組發現，動態細胞譜系啟動是由ERK通過直接增強子調節來驅動的。該研究於2019年11月6日在線發表於國際一流學術期刊《自然》。
研究人員發現細胞外信號調節激酶（ERK）通過直接影響增強子的活性而無需改變轉錄因子的結合，從而可逆地調節胚胎幹細胞（ES細胞）中的轉錄。ERK觸發RNA聚合酶II和相關輔因子與基因和增強子之間可逆的結合和解離，而中介體組分MED24在ERK依賴性轉錄調節中起重要作用。儘管中介體成分的結合直接響應信號，但是多能性因子與誘導和抑制基因的持久結合將它們標記為響應ERK活性波動而被激活和/或重新激活。
在被抑制的基因中，多潛能網絡的幾個核心成分起著驅動其自身表達並維持ES細胞狀態的作用。如果它們的結合丟失，則重新激活轉錄的能力將受到損害。因此，只要維持轉錄因子的佔位，可塑性就保持不變，使細胞能夠區分瞬時信號和持續信號。如果ERK信號持續存在，則多能性轉錄因子水平會因蛋白質更新而降低，並且可能發生不可逆的基因沉默和改變。
據介紹，了解多細胞生物中細胞行為的核心問題是，細胞如何退出一種轉錄狀態並被採納並最終致力於另一種轉錄狀態。成纖維細胞生長因子-細胞外信號調節激酶（FGF-ERK）信號驅動小鼠ES細胞和著床前胚胎向原始內胚層的分化，抑制ERK支持ES細胞自我更新。旁分泌FGF-ERK信號傳導誘導異質性，從而使細胞從多能性可逆地發展為原始內胚層，同時保留其重新進入自我更新的能力。
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