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Dynamic lineage priming is driven via direct enhancer regulation by ERK

Author

Listed:
  • 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
    The University of Manchester)

  • 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)

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.

Suggested Citation

  • William B. Hamilton & Yaron Mosesson & Rita S. Monteiro & Kristina B. Emdal & Teresa E. Knudsen & Chiara Francavilla & Naama Barkai & Jesper V. Olsen & Joshua M. Brickman, 2019. "Dynamic lineage priming is driven via direct enhancer regulation by ERK," Nature, Nature, vol. 575(7782), pages 355-360, November.
  • Handle: RePEc:nat:nature:v:575:y:2019:i:7782:d:10.1038_s41586-019-1732-z
    DOI: 10.1038/s41586-019-1732-z
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    Cited by:

    1. Joyce J. Thompson & Daniel J. Lee & Apratim Mitra & Sarah Frail & Ryan K. Dale & Pedro P. Rocha, 2022. "Extensive co-binding and rapid redistribution of NANOG and GATA6 during emergence of divergent lineages," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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