Erk5 is a key regulator of naïve-­primed transition and Embryonic Stem Cell identity

Charles Williams, Rosalia Fernandez-Alonso, Jinhua Wang, Rachel Toth, Nathanel S Gray, Greg Findlay (Lead / Corresponding author)

Research output: Contribution to journalArticle

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Abstract

Embryonic Stem Cells (ESCs) can self renew or differentiate into all cell types, a phenomenon known as pluripotency. Distinct pluripotent states have been described, termed “naive” and “primed” pluripotency. The mechanisms that control naive‐primed transition are poorly understood. Here, we perform a targeted screen for kinase inhibitors which modulate the naive‐ primed pluripotent transition. We find that selective inhibitors targeting the Erk5 kinase and BET bromodomain family proteins drive ESCs towards primed pluripotency. Using compound selectivity engineering and CRISPR/Cas9 genome editing, we reveal distinct functions for Erk5 and Brd4 in pluripotency regulation. We show that Erk5 signalling maintains ESCs in the naive state, and suppresses progression towards primed pluripotency and neuroectoderm differentiation. Additionally, we identify a specialised role for Erk5 in defining ESC lineage selection, whereby Erk5 inhibits a cardiomyocyte specific differentiation programme. Our data therefore reveal multiple critical functions for Erk5 in controlling ESC identity.
Original languageEnglish
Pages (from-to)1820-1828
Number of pages9
JournalCell Reports
Volume16
Issue number7
Early online date4 Aug 2016
DOIs
Publication statusPublished - 16 Aug 2016

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Embryonic Stem Cells
Stem cells
Phosphotransferases
Clustered Regularly Interspaced Short Palindromic Repeats
Neural Plate
Cell Lineage
Cardiac Myocytes
Genes
Proteins

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title = "Erk5 is a key regulator of na{\"i}ve-­primed transition and Embryonic Stem Cell identity",
abstract = "Embryonic Stem Cells (ESCs) can self renew or differentiate into all cell types, a phenomenon known as pluripotency. Distinct pluripotent states have been described, termed “naive” and “primed” pluripotency. The mechanisms that control naive‐primed transition are poorly understood. Here, we perform a targeted screen for kinase inhibitors which modulate the naive‐ primed pluripotent transition. We find that selective inhibitors targeting the Erk5 kinase and BET bromodomain family proteins drive ESCs towards primed pluripotency. Using compound selectivity engineering and CRISPR/Cas9 genome editing, we reveal distinct functions for Erk5 and Brd4 in pluripotency regulation. We show that Erk5 signalling maintains ESCs in the naive state, and suppresses progression towards primed pluripotency and neuroectoderm differentiation. Additionally, we identify a specialised role for Erk5 in defining ESC lineage selection, whereby Erk5 inhibits a cardiomyocyte specific differentiation programme. Our data therefore reveal multiple critical functions for Erk5 in controlling ESC identity.",
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Erk5 is a key regulator of naïve-­primed transition and Embryonic Stem Cell identity. / Williams, Charles; Fernandez-Alonso, Rosalia; Wang, Jinhua; Toth, Rachel; Gray, Nathanel S; Findlay, Greg (Lead / Corresponding author).

In: Cell Reports, Vol. 16, No. 7, 16.08.2016, p. 1820-1828.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Erk5 is a key regulator of naïve-­primed transition and Embryonic Stem Cell identity

AU - Williams, Charles

AU - Fernandez-Alonso, Rosalia

AU - Wang, Jinhua

AU - Toth, Rachel

AU - Gray, Nathanel S

AU - Findlay, Greg

N1 - Funding: Medical Research Council

PY - 2016/8/16

Y1 - 2016/8/16

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AB - Embryonic Stem Cells (ESCs) can self renew or differentiate into all cell types, a phenomenon known as pluripotency. Distinct pluripotent states have been described, termed “naive” and “primed” pluripotency. The mechanisms that control naive‐primed transition are poorly understood. Here, we perform a targeted screen for kinase inhibitors which modulate the naive‐ primed pluripotent transition. We find that selective inhibitors targeting the Erk5 kinase and BET bromodomain family proteins drive ESCs towards primed pluripotency. Using compound selectivity engineering and CRISPR/Cas9 genome editing, we reveal distinct functions for Erk5 and Brd4 in pluripotency regulation. We show that Erk5 signalling maintains ESCs in the naive state, and suppresses progression towards primed pluripotency and neuroectoderm differentiation. Additionally, we identify a specialised role for Erk5 in defining ESC lineage selection, whereby Erk5 inhibits a cardiomyocyte specific differentiation programme. Our data therefore reveal multiple critical functions for Erk5 in controlling ESC identity.

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