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


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.

SUBMITTER: Yuan B 

PROVIDER: S-EPMC9233711 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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

Yuan Baolei B   Zhou Xuan X   Suzuki Keiichiro K   Ramos-Mandujano Gerardo G   Wang Mengge M   Tehseen Muhammad M   Cortés-Medina Lorena V LV   Moresco James J JJ   Dunn Sarah S   Hernandez-Benitez Reyna R   Hishida Tomoaki T   Kim Na Young NY   Andijani Manal M MM   Bi Chongwei C   Ku Manching M   Takahashi Yuta Y   Xu Jinna J   Qiu Jinsong J   Huang Ling L   Benner Christopher C   Aizawa Emi E   Qu Jing J   Liu Guang-Hui GH   Li Zhongwei Z   Yi Fei F   Ghosheh Yanal Y   Shao Changwei C   Shokhirev Maxim M   Comoli Patrizia P   Frassoni Francesco F   Yates John R JR   Fu Xiang-Dong XD   Esteban Concepcion Rodriguez CR   Hamdan Samir S   Izpisua Belmonte Juan Carlos JC   Li Mo M  

Nature communications 20220625 1


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 in  ...[more]

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