Abstract:
: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.
journal_name
Proc Natl Acad Sci U S Aauthors
Liu Y,Peng J,Sun T,Li N,Zhang L,Ren J,Yuan H,Kan S,Pan Q,Li X,Ding Y,Jiang M,Cong X,Tan M,Ma Y,Fu D,Cai S,Xiao Y,Wang X,Qin Jdoi
10.1073/pnas.1700909114subject
Has Abstractpub_date
2017-05-09 00:00:00pages
E3796-E3805issue
19eissn
0027-8424issn
1091-6490pii
1700909114journal_volume
114pub_type
杂志文章abstract::The ability to integrate visual information over space is a fundamental component of human pattern vision. Regardless of whether it is for detecting luminance contrast or for recognizing objects in a cluttered scene, the position of the target in the visual field governs the size of a window within which visual inform...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
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更新日期:2019-02-26 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:2016-05-24 00:00:00
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doi:10.1073/pnas.95.16.9155
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:1978-06-01 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:1985-09-01 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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doi:10.1073/pnas.82.22.7738
更新日期:1985-11-01 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:2004-08-24 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:1997-03-18 00:00:00