Shape-induced terminal differentiation of human epidermal stem cells requires p38 and is regulated by histone acetylation

TY - JOUR

T1 - Shape-induced terminal differentiation of human epidermal stem cells requires p38 and is regulated by histone acetylation

AU - Connelly, John T

AU - Mishra, Ajay

AU - Gautrot, Julien E

AU - Watt, Fiona M

PY - 2011/11/2

Y1 - 2011/11/2

N2 - 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.

AB - 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.

KW - Acetylation

KW - Cell Differentiation

KW - Cell Shape

KW - Epidermis

KW - Histones

KW - Humans

KW - Serum Response Factor

KW - Stem Cells

KW - Transcription Factor AP-1

KW - p38 Mitogen-Activated Protein Kinases

U2 - 10.1371/journal.pone.0027259

DO - 10.1371/journal.pone.0027259

M3 - Article

C2 - 22073300

SN - 1932-6203

VL - 6

SP - N/A

JO - PLoS ONE

JF - PLoS ONE

IS - 11

M1 - e27259

ER -