Dynamic lineage priming is driven via direct enhancer regulation by ERK

William B. Hamilton, Yaron Mosesson, Rita S. Monteiro, Kristina B. Emdal, Teresa E. Knudsen, Chiara Francavilla, Naama Barkai, Jesper V. Olsen and Joshua M. Brickman ()
Additional contact information
William B. Hamilton: The Novo Nordisk Foundation Center for Stem Cell Biology
Yaron Mosesson: Weizmann Institute of Science
Rita S. Monteiro: The Novo Nordisk Foundation Center for Stem Cell Biology
Kristina B. Emdal: The Novo Nordisk Foundation Center for Protein Research
Teresa E. Knudsen: The Novo Nordisk Foundation Center for Stem Cell Biology
Chiara Francavilla: The Novo Nordisk Foundation Center for Protein Research
Naama Barkai: Weizmann Institute of Science
Jesper V. Olsen: The Novo Nordisk Foundation Center for Protein Research
Joshua M. Brickman: The Novo Nordisk Foundation Center for Stem Cell Biology

Nature, 2019, vol. 575, issue 7782, 355-360

Abstract: 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 FGF–ERK 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.

Date: 2019
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DOI: 10.1038/s41586-019-1732-z

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