Alternative Splicing of MBD2 Supports Self-Renewal in Human Pluripotent Stem Cells
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 st...
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Veröffentlicht in: | Cell stem cell 2014-07, Vol.15 (1), p.92-101 |
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Sprache: | eng |
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Zusammenfassung: | 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 that 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. Although 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 in support of hPSC self-renewal and reprogramming.
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•The splicing factor SFRS2 supports human PSC self-renewal and is a target of OCT4•SFRS2 mediates splicing of MBD2 isoforms that play opposing roles in pluripotency•MBD2a, but not MBD2c, can interact with the NuRD chromatin remodeling complex•OCT4, SFRS2, and MBD2 comprise a positive feedback loop in human PSCs
Alternative splicing plays a central role in regulating pluripotency, and the splicing factor SFRS2, under the control of OCT4, generates splice variants of MDB2 that have opposing roles in maintaining self-renewal and reprogramming. |
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ISSN: | 1934-5909 1875-9777 |
DOI: | 10.1016/j.stem.2014.04.002 |