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论文题目: Epithelial EZH2 serves as an epigenetic determinant in experimental colitis by inhibiting TNF alpha-mediated inflammation and apoptosis
英文论文题目: Epithelial EZH2 serves as an epigenetic determinant in experimental colitis by inhibiting TNF alpha-mediated inflammation and apoptosis
第一作者: Liu, YF; Peng, JJ; Sun, TY; Li, N; Zhang, L; Ren, JL; Yuan, HR; Kan, S; Pan, Q; Li, X; Ding, YF; Jiang, M; Cong, XJ; Tan, MJ; Ma, YS; Fu, D; Cai, SJ; Xiao, YC; Wang, XM; Qin, J
英文第一作者: Liu, YF; Peng, JJ; Sun, TY; Li, N; Zhang, L; Ren, JL; Yuan, HR; Kan, S; Pan, Q; Li, X; Ding, YF; Jiang, M; Cong, XJ; Tan, MJ; Ma, YS; Fu, D; Cai, SJ; Xiao, YC; Wang, XM; Qin, J
联系作者: Qin, J (reprint author), Chinese Acad Sci, Key Lab Stem Cell Biol, CAS Ctr Excellence Mol Cell Sci, Shanghai Inst Biol Sci,Inst Hlth Sci, Shanghai 200031, Peoples R China.
英文联系作者: Qin, J (reprint author), Chinese Acad Sci, Key Lab Stem Cell Biol, CAS Ctr Excellence Mol Cell Sci, Shanghai Inst Biol Sci,Inst Hlth Sci, Shanghai 200031, Peoples R China.
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发表年度: 2017
卷: 114
期: 19
页码: E3796-E3805
摘要: 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 TNF alpha-induced NF kappa B signaling, thereby leading to uncontrolled inflammation. More importantly, we show that EZH2 depletion compromises the protective role of NF-kappa B 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 TNF alpha signaling to promote the inflammatory response and apoptosis in colitis.
英文摘要: 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 TNF alpha-induced NF kappa B signaling, thereby leading to uncontrolled inflammation. More importantly, we show that EZH2 depletion compromises the protective role of NF-kappa B 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 TNF alpha signaling to promote the inflammatory response and apoptosis in colitis.
刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
英文刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
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学科: Multidisciplinary Sciences
英文学科: Multidisciplinary Sciences
影响因子: 9.661
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论文类别: Article
英文论文类别: Article
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