PNAS:中科院上海生科院秦骏研究组揭示组蛋白H3K27三甲基转移酶
2017年4月24日，国际著名学术期刊《美国科学院院刊》在线发表了中国科学院上海生命科学研究院秦骏研究组的研究论文Epithelial EZH2 Serves as an Epigenetic Determinant in Experimental Colitis by Inhibiting TNFα-mediated Inflammation and Apoptosis。博士后刘永峰及博士研究生孙同玉为论文第一作者，秦骏研究员为论文通讯作者。
过度炎症反应以及肠上皮细胞凋亡是导致炎症性肠病的主要原因。Anti-TNFa抗体目前已在临床上用于治疗炎症性肠病。TNFa信号通路一方面可以激活nf-kb而导致过度的炎症反应，但另一方面NF-kb信号的激活也会促进上皮细胞的存活。因此，TNFa信号如何促进肠炎的发生发展还有待进一步阐明。
研究组通过肠道上皮细胞敲除及过表达EZH2并结合小鼠肠炎疾病模型，揭示组蛋白H3K27三甲基化转移酶EZH2在炎症性肠病中的保护功能。研究表明EZH2的缺失导致TRAF2/5表达上调，从而使肠上皮细胞对TNFa更加敏感，导致了更强的炎症反应。调控该TNFa信号的同时，EZH2的缺失解除了其对ITCH的转录抑制。作为c-Flip的E3连接酶，ITCH的高表达使C-Flip稳定性显著降低，减少了其对于Caspase 8介导的细胞凋亡的抑制作用，从而抑制NF-kb对于维持细胞存活的功能。该项工作揭示了在EZH2活性或表达较低的肠炎病人中使用anti-TNFa抗体治疗肠炎可能会有更好的疗效，同时提示EZH2在炎癌反应中可能的重要作用。
图示：EZH2调控肠炎发生发展及机制示意图
原文链接：
Epithelial EZH2 Serves as an Epigenetic Determinant in Experimental Colitis by Inhibiting TNFα-mediated Inflammation and Apoptosis
原文摘要：
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 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.
作者：秦骏
