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Co-regulation of alternative splicing with transcription initiation and termination

ABSTRACT: Nascent RNA processing requires coordination between transcription and splicing, yet the mechanisms underlying this coupling remain unclear. Here, we develop longPASS, a framework to identify and quantify transcription start site (TSS) and polyadenylation site (PAS) usage in long-read RNA sequencing data. In human cells, longPASS reveals thousands of TSS/PAS-associated alternative splicing events (TASEs) and reproducible links between TSS/PAS choice and exon inclusion across genetic perturbations, human tissues and individuals. Co-occurring pairs of TASE-exons and TASE-TSS/PASs tend to be proximal and show enriched RNA-RNA spatial interactions. Large-scale screening shows that RBMX specifically binds PAS-TASE pairs; RBMX depletion disrupts coordinated splicing and PAS usage, whereas canonical splicing-factor depletion has no significant effect. Manipulating RNA polymerase II elongation affects PAS-TASE coupling, with slower elongation increasing co-occurrence. Together, these findings establish genome-wide coupling between alternative splicing and TSS/PAS usage, implicate RBMX and polymerase II elongation in its regulation, and link this process to ageing.

ORGANISM(S): Homo sapiens

PROVIDER: GSE346485 | GEO | 2026/09/09

REPOSITORIES: GEO

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