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

doi:10.1073/pnas.1700909114

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 化学蛋白质组学研究中心

	Epithelial EZH2 serves as an epigenetic determinant in experimental colitis by inhibiting TNF alpha-mediated inflammation and apoptosis
	Liu, Yongfeng 1,2,3; Peng, Junjie 4; Sun, Tongyu 1,2; Li, Ni 1,2; Zhang, Le 5; Ren, Jiale 1,2; Yuan, Huairui 1,2; Kan, Shan 1,2; Pan, Qiang 1,2; Li, Xiang 1,2
刊名	PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
	2017-05-09
卷号	114 期号:19 页码:E3796-E3805
关键词	colitis EZH2 TNF alpha NF-kappa B ITCH
ISSN号	0027-8424
DOI	10.1073/pnas.1700909114
文献子类	Article
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.
资助项目	National Natural Science Foundation of China[31471281] ; National Natural Science Foundation of China[81422030] ; National Natural Science Foundation of China[81502440] ; National Natural Science Foundation of China[31570881] ; Chinese Academy of Sciences[XDB19000000] ; National Key Basic Research Program[2016YFC0902202] ; Thousand Talents Plan[00000000] ; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University[KF-GN-201602] ; State Key Laboratory of Medical Genomics, Collaborative Innovation Center of Systems Biomedicine, Shanghai Jiao Tong University School of Medicine[00000000]
WOS关键词	NF-KAPPA-B ; ULCERATIVE-COLITIS ; INTESTINAL HOMEOSTASIS ; BOWEL-DISEASE ; BIVALENT PROMOTERS ; LINEAGE COMMITMENT ; INNATE IMMUNITY ; JNK ACTIVATION ; CELL-DEATH ; METHYLATION
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	NATL ACAD SCIENCES
WOS记录号	WOS:000400818400009
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272668]
专题	化学蛋白质组学研究中心中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Qin, Jun
作者单位	1.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; 2.Univ Chinese Acad Sci, Shanghai Jiao Tong Univ, Sch Med, Shanghai 200031, Peoples R China; 3.Nanjing Univ, State Key Lab Pharmaceut Biotechnol, Nanjing 210023, Jiangsu, Peoples R China; 4.Fudan Univ, Dept Colorectal Surg, Shanghai Canc Ctr, Shanghai 200032, Peoples R China; 5.Nanjing Med Univ, Dept Immunol, Nanjing 211166, Jiangsu, Peoples R China; 6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 7.Tongji Univ, Sch Med, Shanghai Peoples Hosp 10, Cent Lab Med Res, Shanghai 200072, Peoples R China; 8.Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Hlth Sci, Key Lab Stem Cell Biol, Shanghai 200031, Peoples R China; 9.Shanghai Jiao Tong Univ, Sch Med, Shanghai 200031, Peoples R China
推荐引用方式 GB/T 7714	Liu, Yongfeng,Peng, Junjie,Sun, Tongyu,et al. Epithelial EZH2 serves as an epigenetic determinant in experimental colitis by inhibiting TNF alpha-mediated inflammation and apoptosis[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2017,114(19):E3796-E3805.
APA	Liu, Yongfeng.,Peng, Junjie.,Sun, Tongyu.,Li, Ni.,Zhang, Le.,...&Qin, Jun.(2017).Epithelial EZH2 serves as an epigenetic determinant in experimental colitis by inhibiting TNF alpha-mediated inflammation and apoptosis.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,114(19),E3796-E3805.
MLA	Liu, Yongfeng,et al."Epithelial EZH2 serves as an epigenetic determinant in experimental colitis by inhibiting TNF alpha-mediated inflammation and apoptosis".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 114.19(2017):E3796-E3805.