Diverse epigenetic strategies interact to control epidermal differentiation

Nat Cell Biol. 2012 Jun 24;14(7):753-63. doi: 10.1038/ncb2520.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Antigens, Nuclear
  • CCAAT-Enhancer-Binding Proteins
  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • ING5 protein, human
  • Integrins
  • Multiprotein Complexes
  • Nerve Tissue Proteins
  • RNA, Messenger
  • Transcription Factors
  • Tumor Suppressor Proteins
  • fetal Alzheimer antigen
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Polycomb Repressive Complex 2
  • UHRF1 protein, human
  • Ubiquitin-Protein Ligases
  • Adenosine Triphosphatases
  • SMARCA5 protein, human