Diverse epigenetic strategies interact to control epidermal differentiation

Klaas W Mulder, Xin Wang, Carles Escriu, Yoko Ito, Roland F Schwarz, Jesse Gillis, Gábor Sirokmány, Giacomo Donati, Santiago Uribe-Lewis, Paul Pavlidis, Adele Murrell, Florian Markowetz, Fiona M Watt

Research output: Contribution to journalArticle

95 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)753-63
Number of pages11
JournalNature cell biology
Volume14
Issue number7
Early online date24 Jun 2012
DOIs
Publication statusPublished - Jul 2012

Keywords

  • Adenosine Triphosphatases
  • Antigens, Nuclear
  • Bayes Theorem
  • CCAAT-Enhancer-Binding Proteins
  • Cell Adhesion
  • Cell Differentiation
  • Cells, Cultured
  • Chromatin Assembly and Disassembly
  • Chromosomal Proteins, Non-Histone
  • Cluster Analysis
  • DNA-Binding Proteins
  • Epidermis
  • Epigenesis, Genetic
  • Gene Expression Regulation
  • Gene Regulatory Networks
  • Humans
  • Integrins
  • Keratinocytes
  • Models, Genetic
  • Multiprotein Complexes
  • Nerve Tissue Proteins
  • Polycomb Repressive Complex 2
  • RNA Interference
  • RNA, Messenger
  • Stem Cell Niche
  • Stem Cells
  • Transcription Factors
  • Transfection
  • Tumor Suppressor Proteins

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  • Cite this

    Mulder, K. W., Wang, X., Escriu, C., Ito, Y., Schwarz, R. F., Gillis, J., Sirokmány, G., Donati, G., Uribe-Lewis, S., Pavlidis, P., Murrell, A., Markowetz, F., & Watt, F. M. (2012). Diverse epigenetic strategies interact to control epidermal differentiation. Nature cell biology, 14(7), 753-63. https://doi.org/10.1038/ncb2520