title: Erk5 Is a Key Regulator of Naive-Primed Transition and Embryonic Stem Cell Identity.
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.
authors: The MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors: Charles A C
authors: CA
authors: Williams
authors: The MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors: Rosalia
authors: R
authors: Fernandez-Alonso
authors: 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.
authors: Jinhua
authors: J
authors: Wang
authors: The Division of Signal Transduction Therapy, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors: Rachel
authors: R
authors: Toth
authors: 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.
authors: Nathanael S
authors: NS
authors: Gray
authors: The MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK. Electronic address: g.m.findlay@dundee.ac.uk.
authors: Greg M
authors: GM
authors: Findlay
mesh_terms: D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D064113:CRISPR-Cas Systems; D002454:Cell Differentiation; D002478:Cells, Cultured; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D058732:Embryoid Bodies / Q000166:cytology / Q000378:metabolism; D000072669:Gene Editing; D005786:Gene Expression Regulation; D051379:Mice; D048054:Mitogen-Activated Protein Kinase 7 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D000071317:Nanog Homeobox Protein / Q000235:genetics / Q000378:metabolism; D054258:Neural Plate / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000097584:DNA Methyltransferase 3B; D000092468:Bromodomain Containing Proteins
chemical_list: D001570:Benzodiazepinones; D004248:DNA (Cytosine-5-)-Methyltransferases; D048054:Mitogen-Activated Protein Kinase 7; D000071317:Nanog Homeobox Protein; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D014157:Transcription Factors; D000097584:DNA Methyltransferase 3B; C486694:Brd4 protein, mouse; D000092468:Bromodomain Containing Proteins; C475540:Nanog protein, mouse