@article{55df48518eb047c88a6914e629a18f45,
title = "Alternative splicing of MBD2 supports self-renewal in human pluripotent stem cells",
abstract = "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.",
author = "Yu Lu and Loh, {Yuin Han} and Hu Li and Marcella Cesana and Ficarro, {Scott B.} and Parikh, {Jignesh R.} and Nathan Salomonis and Toh, {Cheng Xu Delon} and Andreadis, {Stelios T.} and Luckey, {C. John} and Collins, {James J.} and Daley, {George Q.} and Marto, {Jarrod A.}",
note = "Funding Information: We thank J. Sahalie for technical assistance, M.W. Lensch for teratoma interpretation, and G. Adelmant for critical reading of the manuscript. Y.-H.L. is supported by the A ∗ STAR Investigator research award. H.L. is supported by Mayo Clinic Center for Individualized Medicine and Mayo Clinic Center for Regenerative Medicine. Generous support for this work was provided (to C.J.L.) by the Pathology Department of the Brigham and Women{\textquoteright}s Hospital and the National Blood Foundation. J.J.C. is supported by Howard Hughes Medical Institute, SysCODE (Systems-based Consortium for Organ Design & Engineering), and NIH grant RL1DE019021. Generous support for this work was provided (to J.A.M.) by the Dana-Farber Cancer Institute, the Harvard Stem Cell Institute (P01GM099117), and the NIH/NINDS P01NS047572. Y.L. acknowledges support from T32HL66987-11. G.Q.D. is supported by the Howard Hughes Medical Institute and NIGMS 5P50GM099117. G.Q.D., J.J.C., and J.A.M. acknowledge support from NIH/NHLBI 5RC2HL102815-02. G.Q.D. serves on the scientific advisory boards of iPierian, Inc., Verastem, Inc., and MPM Capital. ",
year = "2014",
month = jul,
day = "3",
doi = "10.1016/j.stem.2014.04.002",
language = "English (US)",
volume = "15",
pages = "92--101",
journal = "Cell Stem Cell",
issn = "1934-5909",
publisher = "Cell Press",
number = "1",
}