Epithelial EZH2 serves as an epigenetic determinant in experimental colitis by inhibiting TNFα-mediated inflammation and apoptosis
Epithelial EZH2 serves as an epigenetic determinant in experimental colitis by inhibiting TNFα-mediated inflammation and apoptosis
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DOI：
10.1073/pnas.1700909114
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发表时间：
2017-05-09
影响因子：
11.1
通讯作者：
Qin, Jun
中科院分区：
文献类型：
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作者：
Liu, Yongfeng;Peng, Junjie;Qin, Jun
上皮屏障破坏是炎症性肠病（IBD）的主要原因；然而，表观遗传调节肠上皮完整性的机制在很大程度上仍未明确。本研究表明，多梳抑制复合体（PRC2）的催化亚基EZH2对于维持炎症条件下上皮细胞屏障的完整性和稳态是不可或缺的。根据EZH2在患者中的表达降低，IECs中EZH2的失活使小鼠对dss和tnbs诱导的实验性结肠炎敏感。相反，肠上皮中EZH2的过表达使小鼠对结肠炎的抵抗力增强。从机制上讲，在炎症条件下，编码TRAF2/5的基因处于精细调节的二价状态。EZH2缺乏增强这些基因的表达，增强TNF α诱导的NF κ B信号，从而导致不受控制的炎症。更重要的是，我们发现EZH2的缺失通过直接上调ITCH（一种众所周知的降解c-FLIP蛋白的E3连接酶），损害了nf - κ B信号在细胞存活中的保护作用。因此，我们的研究结果强调了EZH2整合TNF α信号的多方面作用以促进结肠炎炎症反应和细胞凋亡的表观遗传机制。
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.