TY - JOUR
T1 - Wiskott-Aldrich syndrome protein forms nuclear condensates and regulates alternative splicing
AU - Yuan, Baolei
AU - Zhou, Xuan
AU - Suzuki, Keiichiro
AU - Ramos-Mandujano, Gerardo
AU - Wang, Mengge
AU - Tehseen, Muhammad
AU - Cortés-Medina, Lorena V.
AU - Moresco, James J.
AU - Dunn, Sarah
AU - Hernandez-Benitez, Reyna
AU - Hishida, Tomoaki
AU - Kim, Na Young
AU - Andijani, Manal M.
AU - Bi, Chongwei
AU - Ku, Manching
AU - Takahashi, Yuta
AU - Xu, Jinna
AU - Qiu, Jinsong
AU - Huang, Ling
AU - Benner, Christopher
AU - Aizawa, Emi
AU - Qu, Jing
AU - Liu, Guang Hui
AU - Li, Zhongwei
AU - Yi, Fei
AU - Ghosheh, Yanal
AU - Shao, Changwei
AU - Shokhirev, Maxim
AU - Comoli, Patrizia
AU - Frassoni, Francesco
AU - Yates, John R.
AU - Fu, Xiang Dong
AU - Esteban, Concepcion Rodriguez
AU - Hamdan, Samir
AU - Li, Mo
AU - Izpisua Belmonte, Juan Carlos
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-022-31220-8
DO - 10.1038/s41467-022-31220-8
M3 - Article
C2 - 35752626
AN - SCOPUS:85132991488
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3646
ER -