Alternative splicing of MBD2 supports self-renewal in human pluripotent stem cells.
Alternative splicing of MBD2 supports self-renewal in human pluripotent stem cells.
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DOI：
10.1016/j.stem.2014.04.002
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发表时间：
2014-07-03
期刊：
影响因子：
23.9
通讯作者：
Marto, Jarrod A.
中科院分区：
文献类型：
--
作者：
Lu, Yu;Loh, Yuin-Han;Li, Hu;Cesana, Marcella;Ficarro, Scott B.;Parikh, Jignesh R.;Salomonis, Nathan;Toh, Cheng-Xu Delon;Andreadis, Stelios T.;Luckey, C. John;Collins, James J.;Daley, George Q.;Marto, Jarrod A.
选择性RNA剪接(AS)调节蛋白质组的多样性，包括几个多潜能基因的异构体特异性表达。在这里，我们整合了全球基因表达和蛋白质组分析，并确定了一个分子特征，表明AS在维持人类多能干细胞(HPSC)自我更新方面发挥着核心作用。我们证明了剪接因子SFRS2是多能性所必需的OCT4靶基因。SFRS2调节甲基CpG结合蛋白Mbd2的AS，Mbd2的异构体在维持多能性和重新编程到多能性方面扮演相反的角色。虽然MDB2a和MBD2c都在OCT4和NANOG启动子上富含，但MBD2a优先与抑制性NuRD染色质重塑因子相互作用并促进hPSC分化，而MBD2c的过表达则促进成纤维细胞重新编程为多能性。MiR-301和miR-302家族通过针对SFRS2和MDB2a提供额外的调节。这些数据表明，OCT4、SFRS2和Mbd2参与了一个正反馈环，调节蛋白质组多样性的复杂性，以支持hPSC的自我更新和重新编程。
Alternative RNA splicing (AS) regulates proteome diversity, including isoform-specific expression of several pluripotency genes. Here, we integrated global gene expression and proteomic analyses and identified a molecular signature suggesting a central role for AS in maintaining human pluripotent stem cell (hPSC) self-renewal. We demonstrate the splicing factor SFRS2 is an OCT4 target gene required for pluripotency. SFRS2 regulates AS of the methyl-CpG-binding protein MBD2, whose isoforms play opposing roles in maintenance of, and reprogramming to, pluripotency. While both MDB2a and MBD2c are enriched at the OCT4 and NANOG promoters, MBD2a preferentially interacts with repressive NuRD chromatin remodeling factors and promotes hPSC differentiation, whereas overexpression of MBD2c enhances reprogramming of fibroblasts to pluripotency. The miR-301 and miR-302 families provide additional regulation by targeting SFRS2 and MDB2a. These data suggest that OCT4, SFRS2, and MBD2 participate in a positive feedback loop, regulating proteome diversity complexity in support of hPSC self-renewal and reprogramming.
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影响因子：
64.5
作者：
Gifford CA;Ziller MJ;Gu H;Trapnell C;Donaghey J;Tsankov A;Shalek AK;Kelley DR;Shishkin AA;Issner R;Zhang X;Coyne M;Fostel JL;Holmes L;Meldrim J;Guttman M;Epstein C;Park H;Kohlbacher O;Rinn J;Gnirke A;Lander ES;Bernstein BE;Meissner A
通讯作者：
Meissner A
影响因子：
64.5
作者：
Kim, Jonghwan;Chu, Jianlin;Orkin, Stuart H.
通讯作者：
Orkin, Stuart H.
影响因子：
23.9
作者：
Hu, Guang;Wade, Paul A.
通讯作者：
Wade, Paul A.
影响因子：
64.5
作者：
Braunschweig U;Gueroussov S;Plocik AM;Graveley BR;Blencowe BJ
通讯作者：
Blencowe BJ
影响因子：
7.4
作者：
Ficarro, Scott B.;Adelmant, Guillaume;Tomar, Maria N.;Zhang, Yi;Cheng, Vincent J.;Marto, Jarrod A.
通讯作者：
Marto, Jarrod A.