![]() Previous research found increased intron retention and decreased productive splicing of mRNA of IFNG and TBX21 in WASP-deficient T H1 cells, which correlated with R-loop accumulation at these loci 11. Mutations or dysregulated expression of RNA SFs could result in altered RNA splicing that is associated with cancer 10. ![]() It is also a complex and fine-tuned process that involves a large number of splicing factors (SFs). Precursor mRNA splicing, a process that removes introns from the primary transcript to generate the mature mRNA, contributes to the expression of above 95% of human genes 9. Despite these advances, the multifaceted functions of WASP remain poorly understood. WASP also functions in transcriptional regulation during differentiation of T helper 1 (TH1) cells 4, 6, 7 and homology-directed repair 8. For example, Drosophila WASH regulates nuclear organization, especially in the heterochromatin compartment 5. It has been revealed recently that WASP family proteins function in the nucleus. Some but not all disease phenotypes can be linked to the actin nucleation function of WASP 1, 4. Mutations in WASP cause Wiskott–Aldrich syndrome (WAS), an X-linked primary immunodeficiency that manifests in microthrombocytopenia, eczema, recurrent infections, autoimmunity and predisposition to malignancy 3. WASP family proteins respond to various cellular signals to promote actin polymerization via the Arp2/3 complex 2. Wiskott–Aldrich syndrome protein (WASP) is the founding member of a family of actin nucleation factors that also include N-WASP (neural WASP), SCAR/WAVE, WHAMM, and WASH 1, 2. 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. The role of WASP in gene body condensates is corroborated by ChIPseq and RIPseq. Using an optogenetic system, we showed that WASP forms phase-separated condensates that encompasses SRSF2, nascent RNA and active Pol II. WASP interacts with dozens of nuclear speckle constituents and constrains SRSF2 mobility. Loss of WASP binding to splicing factor gene promoters frequently leads to aberrant epigenetic activation. These models recapitulated WAS phenotypes and revealed that WASP deficiency causes an upregulation of numerous RNA splicing factors and widespread altered splicing. ![]() ![]() We generated three isogenic WAS models using patient induced pluripotent stem cells and genome editing. ![]() The diverse functions of WASP, the deficiency of which causes Wiskott-Aldrich syndrome (WAS), remain poorly defined. Nature Communications volume 13, Article number: 3646 ( 2022) Wiskott-Aldrich syndrome protein forms nuclear condensates and regulates alternative splicing ![]()
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