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Systematic exploration of dynamic splicing networks reveals conserved multistage regulators of neurogenesis

  1. Author:
    Han, Hong
    Best, Andrew J
    Braunschweig, Ulrich
    Mikolajewicz, Nicholas
    Li, Jack Daiyang
    Roth, Jonathan
    Chowdhury, Fuad
    Mantica, Federica
    Nabeel-Shah, Syed
    Parada, Guillermo
    Brown, Kevin R
    O'Hanlon, Dave
    Wei, Jiarun
    Yao, Yuxi
    Zid, Abdelrahman Abou
    Comsa, Lim Caden
    Jen, Mark
    Wang, Jenny
    Datti, Alessandro
    Gonatopoulos Pournatzis,Thomas
    Weatheritt, Robert J
    Greenblatt, Jack F
    Wrana, Jeffrey L
    Irimia, Manuel
    Gingras, Anne-Claude
    Moffat, Jason
    Blencowe, Benjamin J

  2. Author Address

    Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada. Electronic address: hong.han@utoronto.ca., Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada., Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Dr. Aiguader, 88, Barcelona 08003, Spain., Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Institute for Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada., Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada., Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Center for Cancer Research National Cancer Institute, Frederick, MD 21702-1201, USA., EMBL Australia, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; St. Vincent Clinical School, University of New South Wales, Darlinghurst, NSW 2010, Australia., Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada., Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Dr. Aiguader, 88, Barcelona 08003, Spain; Universitat Pompeu Fabra, Barcelona, Spain; ICREA, Barcelona, Spain., Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Institute for Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada. Electronic address: j.moffat@utoronto.ca., Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: b.blencowe@utoronto.ca.,
    1. Year: 2022
    2. Date: Jul 31
    3. Epub Date: 2022 07 31
  2. Journal: Molecular Cell
    1. 82
    2. 16
    3. Pages: 2982-2999
  4. Type of Article: Article
  1. Abstract:

    Alternative splicing (AS) is a critical regulatory layer; yet, factors controlling functionally coordinated splicing programs during developmental transitions are poorly understood. Here, we employ a screening strategy to identify factors controlling dynamic splicing events important for mammalian neurogenesis. Among previously unknown regulators, Rbm38 acts widely to negatively control neural AS, in part through interactions mediated by the established repressor of splicing, Ptbp1. Puf60, a ubiquitous factor, is surprisingly found to promote neural splicing patterns. This activity requires a conserved, neural-differential exon that remodels Puf60 co-factor interactions. Ablation of this exon rewires distinct AS networks in embryonic stem cells and at different stages of mouse neurogenesis. Single-cell transcriptome analyses further reveal distinct roles for Rbm38 and Puf60 isoforms in establishing neuronal identity. Our results describe important roles for previously unknown regulators of neurogenesis and establish how an alternative exon in a widely expressed splicing factor orchestrates temporal control over cell differentiation. Copyright © 2022. Published by Elsevier Inc.

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External Sources

  1. View Full Text
  2. DOI: 10.1016/j.molcel.2022.06.036
  3. PMID: 35914530
  4. View record in Web of Science®
  5. WOS: 000896064100009
  6. PII : S1097-2765(22)00654-2

Library Notes

  1. Fiscal Year: FY2021-2022
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