Erk5 Is a Key Regulator of Naive-Primed Transition and Embryonic Stem Cell Identity

Charles A C Williams; Rosalia Fernandez-Alonso; Jinhua Wang; Rachel Toth; Nathanael S Gray; Greg M Findlay

doi:10.1016/j.celrep.2016.07.033

Erk5 Is a Key Regulator of Naive-Primed Transition and Embryonic Stem Cell Identity

Cell Rep. 2016 Aug 16;16(7):1820-8. doi: 10.1016/j.celrep.2016.07.033. Epub 2016 Aug 4.

Authors

Charles A C Williams¹, Rosalia Fernandez-Alonso¹, Jinhua Wang², Rachel Toth³, Nathanael S Gray², Greg M Findlay⁴

Affiliations

¹ The MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
² Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
³ The Division of Signal Transduction Therapy, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
⁴ The MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK. Electronic address: [email protected].

Abstract

Embryonic stem cells (ESCs) can self-renew or differentiate into any cell type, a phenomenon known as pluripotency. Distinct pluripotent states, termed naive and primed pluripotency, have been described. However, the mechanisms that control naive-primed pluripotent transition are poorly understood. Here, we perform a targeted screen for kinase inhibitors, which modulate the naive-primed pluripotent transition. We find that XMD compounds, which selectively inhibit Erk5 kinase and BET bromodomain family proteins, drive ESCs toward 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 signaling maintains ESCs in the naive state and suppresses progression toward primed pluripotency and neuroectoderm differentiation. Additionally, we identify a specialized role for Erk5 in defining ESC lineage selection, whereby Erk5 inhibits a cardiomyocyte-specific differentiation program. Our data therefore reveal multiple critical functions for Erk5 in controlling ESC identity.

MeSH terms

Animals
Benzodiazepinones / pharmacology
CRISPR-Cas Systems
Cell Differentiation
Cells, Cultured
DNA (Cytosine-5-)-Methyltransferases / genetics
DNA (Cytosine-5-)-Methyltransferases / metabolism
DNA Methyltransferase 3B
Embryoid Bodies / cytology
Embryoid Bodies / metabolism
Gene Editing
Gene Expression Regulation
Mice
Mitogen-Activated Protein Kinase 7 / antagonists & inhibitors
Mitogen-Activated Protein Kinase 7 / genetics*
Mitogen-Activated Protein Kinase 7 / metabolism
Mouse Embryonic Stem Cells / cytology
Mouse Embryonic Stem Cells / drug effects
Mouse Embryonic Stem Cells / metabolism*
Myocytes, Cardiac / cytology
Myocytes, Cardiac / metabolism
Nanog Homeobox Protein / genetics
Nanog Homeobox Protein / metabolism
Neural Plate / cytology
Neural Plate / metabolism
Nuclear Proteins / genetics*
Nuclear Proteins / metabolism
Pluripotent Stem Cells / cytology
Pluripotent Stem Cells / drug effects
Pluripotent Stem Cells / metabolism*
Protein Kinase Inhibitors / pharmacology
Signal Transduction
Transcription Factors / genetics*
Transcription Factors / metabolism

Substances

Benzodiazepinones
Brd4 protein, mouse
Nanog Homeobox Protein
Nanog protein, mouse
Nuclear Proteins
Protein Kinase Inhibitors
Transcription Factors
DNA (Cytosine-5-)-Methyltransferases
Mitogen-Activated Protein Kinase 7

Grants and funding

MR/N000609/1/MRC_/Medical Research Council/United Kingdom