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Wiskott-Aldrich syndrome protein forms nuclear condensates and regulates alternative splicing

Author

Listed:
  • Baolei Yuan

    (King Abdullah University of Science and Technology (KAUST))

  • Xuan Zhou

    (King Abdullah University of Science and Technology (KAUST))

  • Keiichiro Suzuki

    (Gene Expression Laboratory, Salk Institute for Biological Studies
    Osaka University)

  • Gerardo Ramos-Mandujano

    (King Abdullah University of Science and Technology (KAUST))

  • Mengge Wang

    (King Abdullah University of Science and Technology (KAUST))

  • Muhammad Tehseen

    (King Abdullah University of Science and Technology (KAUST))

  • Lorena V. Cortés-Medina

    (King Abdullah University of Science and Technology (KAUST))

  • James J. Moresco

    (Scripps Research Institute)

  • Sarah Dunn

    (The Waitt Advanced Biophotonics Core Facility, Salk Institute for Biological Studies)

  • Reyna Hernandez-Benitez

    (Gene Expression Laboratory, Salk Institute for Biological Studies
    Altos Labs, Inc. 5510 Morehouse Drive, Suite 300)

  • Tomoaki Hishida

    (Gene Expression Laboratory, Salk Institute for Biological Studies
    Wakayama Medical University)

  • Na Young Kim

    (Gene Expression Laboratory, Salk Institute for Biological Studies)

  • Manal M. Andijani

    (King Abdullah University of Science and Technology (KAUST))

  • Chongwei Bi

    (King Abdullah University of Science and Technology (KAUST))

  • Manching Ku

    (Next-generation sequencing core, Salk Institute for Biological Studies)

  • Yuta Takahashi

    (Gene Expression Laboratory, Salk Institute for Biological Studies
    University of Tsukuba)

  • Jinna Xu

    (King Abdullah University of Science and Technology (KAUST))

  • Jinsong Qiu

    (University of California at San Diego)

  • Ling Huang

    (Integrative Genomics and Bioinformatics Core, Salk Institute for Biological Studies)

  • Christopher Benner

    (Integrative Genomics and Bioinformatics Core, Salk Institute for Biological Studies)

  • Emi Aizawa

    (Gene Expression Laboratory, Salk Institute for Biological Studies
    Osaka University)

  • Jing Qu

    (Chinese Academy of Sciences)

  • Guang-Hui Liu

    (Chinese Academy of Sciences)

  • Zhongwei Li

    (Gene Expression Laboratory, Salk Institute for Biological Studies
    University of Southern California)

  • Fei Yi

    (Gene Expression Laboratory, Salk Institute for Biological Studies
    Ambys Medicines)

  • Yanal Ghosheh

    (King Abdullah University of Science and Technology (KAUST))

  • Changwei Shao

    (University of California at San Diego)

  • Maxim Shokhirev

    (Integrative Genomics and Bioinformatics Core, Salk Institute for Biological Studies)

  • Patrizia Comoli

    (Pediatric Hematology/Oncology and Cell Factory, Fondazione IRCCS Policlinico San Matteo)

  • Francesco Frassoni

    (Instituto G. Gaslini Children Hospital Scientific Institute)

  • John R. Yates

    (Scripps Research Institute)

  • Xiang-Dong Fu

    (University of California at San Diego)

  • Concepcion Rodriguez Esteban

    (Gene Expression Laboratory, Salk Institute for Biological Studies
    Altos Labs, Inc. 5510 Morehouse Drive, Suite 300)

  • Samir Hamdan

    (King Abdullah University of Science and Technology (KAUST))

  • Juan Carlos Izpisua Belmonte

    (King Abdullah University of Science and Technology (KAUST)
    Gene Expression Laboratory, Salk Institute for Biological Studies
    Altos Labs, Inc. 5510 Morehouse Drive, Suite 300)

  • Mo Li

    (King Abdullah University of Science and Technology (KAUST))

Abstract

The diverse functions of WASP, the deficiency of which causes Wiskott-Aldrich syndrome (WAS), remain poorly defined. We generated three isogenic WAS models using patient induced pluripotent stem cells and genome editing. These models recapitulated WAS phenotypes and revealed that WASP deficiency causes an upregulation of numerous RNA splicing factors and widespread altered splicing. Loss of WASP binding to splicing factor gene promoters frequently leads to aberrant epigenetic activation. WASP interacts with dozens of nuclear speckle constituents and constrains SRSF2 mobility. Using an optogenetic system, we showed that WASP forms phase-separated condensates that encompasses SRSF2, nascent RNA and active Pol II. The role of WASP in gene body condensates is corroborated by ChIPseq and RIPseq. Together our data reveal that WASP is a nexus regulator of RNA splicing that controls the transcription of splicing factors epigenetically and the dynamics of the splicing machinery through liquid-liquid phase separation.

Suggested Citation

  • Baolei Yuan & Xuan Zhou & Keiichiro Suzuki & Gerardo Ramos-Mandujano & Mengge Wang & Muhammad Tehseen & Lorena V. Cortés-Medina & James J. Moresco & Sarah Dunn & Reyna Hernandez-Benitez & Tomoaki Hish, 2022. "Wiskott-Aldrich syndrome protein forms nuclear condensates and regulates alternative splicing," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31220-8
    DOI: 10.1038/s41467-022-31220-8
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    References listed on IDEAS

    as
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    2. Guang-Hui Liu & Basam Z. Barkho & Sergio Ruiz & Dinh Diep & Jing Qu & Sheng-Lian Yang & Athanasia D. Panopoulos & Keiichiro Suzuki & Leo Kurian & Christopher Walsh & James Thompson & Stephanie Boue & , 2011. "Recapitulation of premature ageing with iPSCs from Hutchinson–Gilford progeria syndrome," Nature, Nature, vol. 472(7342), pages 221-225, April.
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    4. Guang-Hui Liu & Keiichiro Suzuki & Mo Li & Jing Qu & Nuria Montserrat & Carolina Tarantino & Ying Gu & Fei Yi & Xiuling Xu & Weiqi Zhang & Sergio Ruiz & Nongluk Plongthongkum & Kun Zhang & Shigeo Masu, 2014. "Modelling Fanconi anemia pathogenesis and therapeutics using integration-free patient-derived iPSCs," Nature Communications, Nature, vol. 5(1), pages 1-17, September.
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    Full references (including those not matched with items on IDEAS)

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