RNA剪接與表觀協同失調促進白血病發生
作者：
小柯機器人發布時間：2019/10/3 21:04:21
美國紀念斯隆-凱特琳癌症中心Omar Abdel-Wahab小組近日發現，RNA剪接和表觀遺傳調控的協調變化驅動白血病發生。相關論文2019年10月2日在線發表於《自然》雜誌。
通過分析982例急性髓性白血病患者的轉錄組，研究人員發現IDH2和SRSF2基因突變的頻繁重疊，通過對表觀基因組和RNA剪接的協同作用共同促進白血病的發生。儘管IDH2或SRSF2中的突變賦予明顯的剪接變化，但突變體IDH2的共表達改變了突變體SRSF2的剪接效果，並導致比單獨的任一突變更明顯的剪接變化。與此相一致，突變體IDH2和SRSF2的共表達導致具有體內增殖特徵的致死性骨髓增生異常，並且以單獨兩種突變均未觀察到的方式增強了自我更新。IDH2和SRSF2雙突變細胞表現出異常的剪接和INTS3基因（整合子複合物3的成員）的表達降低，與RNA聚合酶II的失速增加相一致。異常的INTS3剪接與突變IDH2協同促成白血病的發生，並且依賴於突變SRSF2與INTS3 mRNA中的順式元件結合以及INTS3的DNA甲基化增加。
這些數據確定了一部分白血病中表觀遺傳狀態的改變和剪接之間的致病性互作，提供了剪接因子突變驅動髓系惡性腫瘤發展的功能證據，並確定了剪接體變化是IDH2突變性白血病發生的介導者。
據了解，轉錄和mRNA剪接是控制基因表達的關鍵步驟，而調節這些過程中的每一個的基因突變在白血病中都很常見。儘管影響白血病的表觀遺傳調控和剪接的突變經常重疊，但尚不清楚這些過程如何相互影響以促進白血病的發生，據研究人員所知，沒有功能證據表明RNA剪接因子中的突變會引發白血病。
附：英文原文
Title: Coordinated alterations in RNA splicing and epigenetic regulation drive leukaemogenesis
Author: Akihide Yoshimi, Kuan-Ting Lin, Daniel H. Wiseman, Mohammad Alinoor Rahman, Alessandro Pastore, Bo Wang, Stanley Chun-Wei Lee, Jean-Baptiste Micol, Xiao Jing Zhang, Stephane de Botton, Virginie Penard-Lacronique, Eytan M. Stein, Hana Cho, Rachel E. Miles, Daichi Inoue, Todd R. Albrecht, Tim C. P. Somervaille, Kiran Batta, Fabio Amaral, Fabrizio Simeoni, Deepti P. Wilks, Catherine Cargo, Andrew M. Intlekofer, Ross L. Levine, Heidi Dvinge, Robert K. Bradley, Eric J. Wagner, Adrian R. Krainer, Omar Abdel-Wahab
Issue&Volume: 2019-10-02
Abstract:
Transcription and pre-mRNA splicing are key steps in the control of gene expression and mutations in genes regulating each of these processes are common in leukaemia1,2. Despite the frequent overlap of mutations affecting epigenetic regulation and splicing in leukaemia, how these processes influence one another to promote leukaemogenesis is not understood and, to our knowledge, there is no functional evidence that mutations in RNA splicing factors initiate leukaemia. Here, through analyses of transcriptomes from 982 patients with acute myeloid leukaemia, we identified frequent overlap of mutations in IDH2 and SRSF2 that together promote leukaemogenesis through coordinated effects on the epigenome and RNA splicing. Whereas mutations in either IDH2 or SRSF2 imparted distinct splicing changes, co-expression of mutant IDH2 altered the splicing effects of mutant SRSF2 and resulted in more profound splicing changes than either mutation alone. Consistent with this, co-expression of mutant IDH2 and SRSF2 resulted in lethal myelodysplasia with proliferative features in vivo and enhanced self-renewal in a manner not observed with either mutation alone. IDH2 and SRSF2 double-mutant cells exhibited aberrant splicing and reduced expression of INTS3, a member of the integrator complex3, concordant with increased stalling of RNA polymerase II (RNAPII). Aberrant INTS3 splicing contributed to leukaemogenesis in concert with mutant IDH2 and was dependent on mutant SRSF2 binding to cis elements in INTS3 mRNA and increased DNA methylation of INTS3. These data identify a pathogenic crosstalk between altered epigenetic state and splicing in a subset of leukaemias, provide functional evidence that mutations in splicing factors drive myeloid malignancy development, and identify spliceosomal changes as a mediator of IDH2-mutant leukaemogenesis.
DOI: 10.1038/s41586-019-1618-0
Source:https://www.nature.com/articles/s41586-019-1618-0