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

Significance TNFα is the key cytokine implicated in inflammatory bowel disease. However, TNFα is not always proinflammatory, because TNFα-activated NF-κB induces prosurvival proteins, including c-FLIP, to constrain caspase 8 activation. Here we report that epithelial EZH2 integrates the multifaceted effects of TNFα signaling to promote inflammation and apoptosis in colitis. EZH2 reduction directly stimulates TRAF2/5 expression to enhance TNFα-induced NF-κB signaling. More importantly, EZH2 deficiency up-regulates the expression of the E3 ligase ITCH to degrade the c-FLIP protein, thereby antagonizing the prosurvival role of NF-κB. Taken together, our results indicate that EZH2 serves as an epigenetic brake to modulate TNFα functions in colitis. Moreover, the data suggest that patients with lower levels of EZH2 might have a better response to anti-TNFα therapy. 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.