Alternative splicing of MBD2 supports self-renewal in human pluripotent stem cells

Yu Lu, Yuin Han Loh, Hu Li, Marcella Cesana, Scott B. Ficarro, Jignesh R. Parikh, Nathan Salomonis, Cheng Xu Delon Toh, Stelios T. Andreadis, C. John Luckey, James J. Collins, George Q. Daley, Jarrod A. Marto

Research output: Contribution to journalArticlepeer-review

70 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)92-101
Number of pages10
JournalCell Stem Cell
Issue number1
StatePublished - Jul 3 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology


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