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Diverse epigenetic strategies interact to control epidermal differentiation

Item Type:Article
Title:Diverse epigenetic strategies interact to control epidermal differentiation
Creators Name:Mulder, K.W. and Wang, X. and Escriu, C. and Ito, Y. and Schwarz, R.F. and Gillis, J. and Sirokmany, G. and Donati, G. and Uribe-Lewis, S. and Pavlidis, P. and Murrell, A. and Markowetz, F. and Watt, F.M.
Abstract:It is becoming clear that interconnected functional gene networks, rather than individual genes, govern stem cell self-renewal and differentiation. To identify epigenetic factors that impact on human epidermal stem cells we performed siRNA-based genetic screens for 332 chromatin modifiers. We developed a Bayesian mixture model to predict putative functional interactions between epigenetic modifiers that regulate differentiation. We discovered a network of genetic interactions involving EZH2, UHRF1 (both known to regulate epidermal self-renewal), ING5 (a MORF complex component), BPTF and SMARCA5 (NURF complex components). Genome-wide localization and global mRNA expression analysis revealed that these factors impact two distinct but functionally related gene sets, including integrin extracellular matrix receptors that mediate anchorage of epidermal stem cells to their niche. Using a competitive epidermal reconstitution assay we confirmed that ING5, BPTF, SMARCA5, EZH2 and UHRF1 control differentiation under physiological conditions. Thus, regulation of distinct gene expression programs through the interplay between diverse epigenetic strategies protects epidermal stem cells from differentiation.
Keywords:Adenosine Triphosphatases, Bayes Theorem, CCAAT-Enhancer-Binding Proteins, Cell Adhesion, Cell Differentiation, Chromatin Assembly and Disassembly, Cluster Analysis, Cultured Cells, DNA-Binding Proteins, Epidermis, Gene Expression Regulation, Gene Regulatory Networks, Genetic Epigenesis, Genetic Models, Integrins, Keratinocytes, Messenger RNA, Multiprotein Complexes, Nerve Tissue Proteins, Non-Histone Chromosomal Proteins, Nuclear Antigens, Polycomb Repressive Complex 2, RNA Interference, Stem Cell Niche, Stem Cells, Transcription Factors, Transfection, Tumor Suppressor Proteins
Source:Nature Cell Biology
Publisher:Nature Publishing Group
Page Range:753-763
Date:24 June 2012
Official Publication:https://doi.org/10.1038/ncb2520
PubMed:View item in PubMed

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