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Histone methyltransferase SETD2 modulates alternative splicing to inhibit intestinal tumorigenesis
The Journal of Clinical Investigation ( IF 13.3 ) Pub Date : 2017-08-21 , DOI: 10.1172/jci94292
Huairui Yuan , Ni Li , Da Fu , Jiale Ren , Jingyi Hui , Junjie Peng , Yongfeng Liu , Tong Qiu , Min Jiang , Qiang Pan , Ying Han , Xiaoming Wang , Qintong Li , Jun Qin

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.

中文翻译:

组蛋白甲基转移酶SETD2调节选择性剪接以抑制肠道肿瘤发生

组蛋白H3K36甲基转移酶SETD2在多种人类肿瘤中经常发生突变或缺失。尽管如此,SETD2丢失在肿瘤发生中的作用仍不清楚。在这里,我们发现SETD2抵消了Wnt信号传导,其失活促进了结直肠癌(CRC)小鼠模型的肠道肿瘤发生。在稳态下,肠稳态不需要SETD2。但是,照射后,Setd2的基因失活小鼠肠上皮细胞的上皮促进了肠干/祖细胞的自我更新以及组织再生。此外,在Wnt信号传导失调的情况下,SETD2的耗尽增强了对肿瘤发生的敏感性。机理表征表明,SETD2下调影响涉及肿瘤发生的基因子集的选择性剪接。重要的是,我们发现SETD2切除可减少杂乱无章的片段极性蛋白2(DVL2)pre-mRNA的内含子保留,否则该序列会因无义介导的衰变而降解,从而增强Wnt信号传导。由CRC患者队列分析进一步证实了SETD2介导的信号级联反应。一起,
更新日期:2017-09-08
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