Splicing switch of an epigenetic regulator by RNA helicases promotes tumor-cell invasiveness
Splicing switch of an epigenetic regulator by RNA helicases promotes tumor-cell invasiveness
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DOI：
10.1038/nsmb.2390
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发表时间：
2012-11-01
影响因子：
16.8
通讯作者：
Auboeuf, Didier
中科院分区：
文献类型：
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作者：
Dardenne, Etienne;Pierredon, Sandra;Auboeuf, Didier
表观遗传和剪接调控都有助于肿瘤的进展，但这两个水平的基因表达调控在发病机制中的潜在联系尚不清楚。在这里，我们报告了小鼠和人类的RNA解旋酶Ddx17和Ddx5通过调节几种dna和染色质结合因子（包括macroH2A1组蛋白）的选择性剪接来促进肿瘤细胞的侵袭性。我们发现macroH2A1剪接异构体对一组参与氧化还原代谢的基因的转录有差异调节。特别是，编码细胞外超氧化物歧化酶并参与细胞迁移的SOD3基因被macroH2A1剪接异构体以相反的方式调节。这些发现揭示了一个新的调控途径，其中剪接因子控制组蛋白变异亚型的表达，进而驱动转录程序将肿瘤细胞转换为侵袭性表型。
Both epigenetic and splicing regulation contribute to tumor progression, but the potential links between these two levels of gene-expression regulation in pathogenesis are not well understood. Here, we report that the mouse and human RNA helicases Ddx17 and Ddx5 contribute to tumor-cell invasiveness by regulating alternative splicing of several DNA-and chromatin-binding factors, including the macroH2A1 histone. We show that macroH2A1 splicing isoforms differentially regulate the transcription of a set of genes involved in redox metabolism. In particular, the SOD3 gene that encodes the extracellular superoxide dismutase and plays a part in cell migration is regulated in an opposite manner by macroH2A1 splicing isoforms. These findings reveal a new regulatory pathway in which splicing factors control the expression of histone variant isoforms that in turn drive a transcription program to switch tumor cells to an invasive phenotype.