Diverse epigenetic strategies interact to control epidermal differentiation

• Published in: Nature cell biology Vol. 14; no. 7; pp. 753 - 763
• Main Authors: Mulder, Klaas W., Wang, Xin, Escriu, Carles, Ito, Yoko, Schwarz, Roland F., Gillis, Jesse, Sirokmány, Gábor, Donati, Giacomo, Uribe-Lewis, Santiago, Pavlidis, Paul, Murrell, Adele, Markowetz, Florian, Watt, Fiona M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2012; Nature Publishing Group
• Subjects: 631/136/532/1360; 631/1647/1407/505; 631/208/176; Adenosine Triphosphatases - genetics; Adenosine Triphosphatases - metabolism; Antigens, Nuclear - genetics; Antigens, Nuclear - metabolism; Bayes Theorem; Biology; Biomedical and Life Sciences; Cancer Research; CCAAT-Enhancer-Binding Proteins - genetics; CCAAT-Enhancer-Binding Proteins - metabolism; Cell Adhesion - genetics; Cell Biology; Cell cycle; Cell differentiation; Cell Differentiation - genetics; Cell division; Cells, Cultured; Chromatin Assembly and Disassembly; Chromosomal Proteins, Non-Histone - genetics; Chromosomal Proteins, Non-Histone - metabolism; Cluster Analysis; Developmental Biology; DNA methylation; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Enhancer of Zeste Homolog 2 Protein; Epidermal Cells; Epigenesis, Genetic; Epigenetic inheritance; Epigenetics; Extracellular matrix; Gene Expression Regulation; Gene Regulatory Networks; Genes; Genetic aspects; Genomics; Humans; Integrins - genetics; Integrins - metabolism; Keratinocytes - metabolism; Life Sciences; Medical research; Models, Genetic; Multiprotein Complexes; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Physiological aspects; Physiology; Polycomb Repressive Complex 2; Research centers; resource; RNA Interference; RNA, Messenger - metabolism; Stem Cell Niche - genetics; Stem Cells; Stem Cells - metabolism; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Transfection; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; United Kingdom; United Kingdom > UK
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/ncb2520

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. Watt and colleagues carried out an RNAi screen to identify epigenetic modifiers involved in the control of epidermal differentiation. They delineate a network of genetic interactions using a Bayesian mixture model approach, and uncover two complexes of modifiers that differentially affect self-renewal and differentiation of epidermal stem cells.