机构：[1]The Key Laboratory of Stem Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/ Shanghai Jiao Tong University School of Medicine, University of Chinese Academy of Sciences, Shanghai, China.[2]Central Laboratory for Medical Research, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China.[3]State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.[4]Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.[5]Department of Obstetrics, Gynecology and Pediatrics, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, China.[6]Department of Immunology, Nanjing Medical University, Nanjing, China.
The histone H3K36 methyltransferase SETD2 is frequently mutated or deleted in a variety of human tumors. Nevertheless, the role of SETD2 loss in oncogenesis remains largely undefined. Here, we found that SETD2 counteracts Wnt signaling and its inactivation promotes intestinal tumorigenesis in mouse models of colorectal cancer (CRC). SETD2 was not required for intestinal homeostasis under steady state; however, upon irradiation, genetic inactivation of Setd2 in mouse intestinal epithelium facilitated the self-renewal of intestinal stem/progenitor cells as well as tissue regeneration. Furthermore, depletion of SETD2 enhanced the susceptibility to tumorigenesis in the context of dysregulated Wnt signaling. Mechanistic characterizations indicated that SETD2 downregulation affects the alternative splicing of a subset of genes implicated in tumorigenesis. Importantly, we uncovered that SETD2 ablation reduces intron retention of dishevelled segment polarity protein 2 (DVL2) pre-mRNA, which would otherwise be degraded by nonsense-mediated decay, thereby augmenting Wnt signaling. The signaling cascades mediated by SETD2 were further substantiated by a CRC patient cohort analysis. Together, our studies highlight SETD2 as an integral regulator of Wnt signaling through epigenetic regulation of RNA processing during tissue regeneration and tumorigenesis.
基金：
We thank Sophia Tsai and Ming-Jer Tsai for critical comments and Li Li for Setd2 flox mice. This work was supported by grants from the National Natural Science Foundation of China (31471281 and 81422030 to JQ, 81502440 to MJ, 81671115 and 81330054 to QL), the Chinese Academy of Sciences (QYZDB-SSW-SMC052), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB19000000), and the National Key Basic Research Program (2016YFC0902202). JQ is a scholar of the National 1000 Young Talents Program of China.
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2017]版：
大类|1 区医学
小类|1 区医学：研究与实验
最新[2023]版：
大类|1 区医学
小类|1 区医学：研究与实验
第一作者：
第一作者机构：[1]The Key Laboratory of Stem Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/ Shanghai Jiao Tong University School of Medicine, University of Chinese Academy of Sciences, Shanghai, China.
通讯作者：
通讯机构：[1]The Key Laboratory of Stem Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/ Shanghai Jiao Tong University School of Medicine, University of Chinese Academy of Sciences, Shanghai, China.[*1]The Key Laboratory of Stem Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Health Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China
推荐引用方式(GB/T 7714)：
Huairui Yuan ,Ni Li ,Da Fu ,et al.Histone methyltransferase SETD2 modulates alternative splicing to inhibit intestinal tumorigenesis.[J].JOURNAL OF CLINICAL INVESTIGATION.2017,127(9):3375-3391.doi:10.1172/JCI94292.
APA：
Huairui Yuan,,Ni Li,,Da Fu,,Jiale Ren,,Jingyi Hui,...&Jun Qin.(2017).Histone methyltransferase SETD2 modulates alternative splicing to inhibit intestinal tumorigenesis..JOURNAL OF CLINICAL INVESTIGATION,127,(9)
MLA：
Huairui Yuan,,et al."Histone methyltransferase SETD2 modulates alternative splicing to inhibit intestinal tumorigenesis.".JOURNAL OF CLINICAL INVESTIGATION 127..9(2017):3375-3391
医学