title: Shape-induced terminal differentiation of human epidermal stem cells requires p38 and is regulated by histone acetylation.
abstract: Engineered model substrates are powerful tools for examining interactions between stem cells and their microenvironment. Using this approach, we have previously shown that restricted cell adhesion promotes terminal differentiation of human epidermal stem cells via activation of serum response factor (SRF) and transcription of AP-1 genes. Here we investigate the roles of p38 MAPK and histone acetylation. Inhibition of p38 activity impaired SRF transcriptional activity and shape-induced terminal differentiation of human keratinocytes. In addition, inhibiting p38 reduced histone H3 acetylation at the promoters of SRF target genes, FOS and JUNB. Although histone acetylation correlated with SRF transcriptional activity and target gene expression, treatment with the histone de-acetylase inhibitor, trichostatin A (TSA) blocked terminal differentiation on micro-patterned substrates and in suspension. TSA treatment simultaneously maintained expression of LRIG1, TP63, and ITGB1. Therefore, global histone de-acetylation represses stem cell maintenance genes independent of SRF. Our studies establish a novel role for extrinsic physical cues in the regulation of chromatin remodeling, transcription, and differentiation of human epidermal stem cells.
authors.affiliation: Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom. j.connelly@qmul.ac.uk
authors.forename: John T
authors.initials: JT
authors.lastname: Connelly
authors.forename: Ajay
authors.initials: A
authors.lastname: Mishra
authors.forename: Julien E
authors.initials: JE
authors.lastname: Gautrot
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Watt
mesh_terms: D000107:Acetylation; D002454:Cell Differentiation; D048430:Cell Shape; D000078404:Epidermal Cells; D004817:Epidermis / Q000201:enzymology; D006657:Histones / Q000378:metabolism*; D006801:Humans; D026362:Serum Response Factor / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000201:enzymology; D018808:Transcription Factor AP-1 / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D006657:Histones; D026362:Serum Response Factor; D018808:Transcription Factor AP-1; D048051:p38 Mitogen-Activated Protein Kinases
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