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

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 Hishida, Na Young Kim, Manal M. Andijani, Chongwei Bi, Manching Ku, Yuta Takahashi, Jinna Xu, Jinsong Qiu, Ling Huang, Christopher BennerEmi Aizawa, Jing Qu, Guang Hui Liu, Zhongwei Li, Fei Yi, Yanal Ghosheh, Changwei Shao, Maxim Shokhirev, Patrizia Comoli, Francesco Frassoni, John R. Yates, Xiang Dong Fu, Concepcion Rodriguez Esteban, Samir Hamdan, Mo Li, Juan Carlos Izpisua Belmonte

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Article number3646
JournalNature communications
Volume13
Issue number1
DOIs
StatePublished - Dec 2022
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • General
  • Physics and Astronomy(all)

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