Epithelial EZH2 serves as an epigenetic determinant in experimental colitis by inhibiting TNFα-mediated inflammation and apoptosis

Proc Natl Acad Sci U S A. 2017 May 9;114(19):E3796-E3805. doi: 10.1073/pnas.1700909114. Epub 2017 Apr 24.


Epithelial barrier disruption is a major cause of inflammatory bowel disease (IBD); however, the mechanism through which epigenetic regulation modulates intestinal epithelial integrity remains largely undefined. Here we show that EZH2, the catalytic subunit of polycomb repressive complex (PRC2), is indispensable for maintaining epithelial cell barrier integrity and homeostasis under inflammatory conditions. In accordance with reduced EZH2 expression in patients, the inactivation of EZH2 in IECs sensitizes mice to DSS- and TNBS-induced experimental colitis. Conversely, EZH2 overexpression in the intestinal epithelium renders mice more resistant to colitis. Mechanistically, the genes encoding TRAF2/5 are held in a finely tuned bivalent status under inflammatory conditions. EZH2 deficiency potentiates the expression of these genes to enhance TNFα-induced NF-κB signaling, thereby leading to uncontrolled inflammation. More importantly, we show that EZH2 depletion compromises the protective role of NF-κB signaling in cell survival by directly up-regulating ITCH, a well-known E3 ligase that degrades the c-FLIP protein. Thus, our findings highlight an epigenetic mechanism by which EZH2 integrates the multifaceted effects of TNFα signaling to promote the inflammatory response and apoptosis in colitis.

Keywords: EZH2; ITCH; NF-κB; TNFα; colitis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
  • CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
  • Colitis / chemically induced
  • Colitis / genetics
  • Colitis / metabolism*
  • Colitis / pathology
  • Dextran Sulfate / toxicity
  • Enhancer of Zeste Homolog 2 Protein / genetics
  • Enhancer of Zeste Homolog 2 Protein / metabolism*
  • Epigenesis, Genetic*
  • Humans
  • Inflammation / chemically induced
  • Inflammation / genetics
  • Inflammation / metabolism
  • Inflammation / pathology
  • Intestinal Mucosa / metabolism*
  • Intestinal Mucosa / pathology
  • Mice
  • Mice, Knockout
  • NF-kappa B / genetics
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Signal Transduction*
  • TNF Receptor-Associated Factor 2 / genetics
  • TNF Receptor-Associated Factor 2 / metabolism
  • TNF Receptor-Associated Factor 5 / genetics
  • TNF Receptor-Associated Factor 5 / metabolism
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism


  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Cflar protein, mouse
  • NF-kappa B
  • PSMD2 protein, human
  • Repressor Proteins
  • TNF Receptor-Associated Factor 2
  • TNF Receptor-Associated Factor 5
  • TRAF2 protein, mouse
  • TRAF5 protein, human
  • Tumor Necrosis Factor-alpha
  • Dextran Sulfate
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Ezh2 protein, mouse
  • ITCH protein, human
  • Itch protein, mouse
  • Ubiquitin-Protein Ligases