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.

WASP 的多种功能，其缺乏会导致 Wiskott-Aldrich 综合征 (WAS)，仍然不明确。我们使用患者诱导的多能干细胞和基因组编辑生成了三个等基因 WAS 模型。这些模型概括了 WAS 表型，并揭示 WASP 缺乏会导致许多 RNA 剪接因子的上调和广泛的剪接改变。WASP 与剪接因子基因启动子结合的缺失经常导致异常的表观遗传激活。WASP 与数十种核散斑成分相互作用并限制 SRSF2 的移动性。使用光遗传学系统，我们发现 WASP 形成包含 SRSF2、新生 RNA 和活性 Pol II 的相分离凝聚物。ChIPseq 和 RIPseq 证实了 WASP 在基因体凝聚物中的作用。