LncRNA-splicing factor condensates regulate hypoxia-responsive pre-mRNA processing near nuclear speckles

The alternative splicing (AS) of pre-mRNA regulates key cellular processes, and its dysregulation is linked to tumorigenesis. Hypoxia, a common feature of malignant tumors, triggers AS in thousands of genes. The mechanisms controlling hypoxia-responsive AS remain unclear. We observe that hypoxia-responsive spliced exons exhibit characteristics of inefficient splicing, and the genes encoding these transcripts are pre-positioned near nuclear speckles-the membraneless nuclear bodies that boost splicing. The speckle-enriched long noncoding RNA (lncRNA) MALAT1 (Metastasis-associated lung adenocarcinoma transcript 1), induced during hypoxia, associates with the hypoxia-responsive genes. Furthermore, MALAT1 promotes AS by modulating the interaction between the SR family of splicing factor 1 (SRSF1) and pre-mRNAs. Mechanistically, MALAT1 promotes the condensation of SRSF1, and the condensates are preferentially recognized and recruited by RNA polymerase II (RNAPII). Overall, our results demonstrate that MALAT1 dictates hypoxia-induced AS by organizing splicing factor condensates near speckles to enable the efficient RNAPII-mediated recruitment of splicing factors to pre-mRNAs.