A splicing factor-cohesin regulatory link connects RNA processing to cohesin-dependent genome folding [CUT&Tag]

Using complementary proteomic approaches, we identify a group of pre-mRNA splicing factors that are spatially proximal to the cohesin loader MAU2 and physically associate with cohesin. Focusing on CDC5L, we show that its acute depletion in human cells perturbs pre-mRNA processing and reduces cohesinSTAG2 occupancy on chromatin.

These changes are accompanied by weakened chromatin interactions within topological domains and a redistribution of chromatin loops associated with cohesinSTAG1. At the molecular level, CDC5L is enriched at active promoters and enhancers, while biochemical fractionation indicates reduced chromatin association of NIPBL, a key regulator of cohesin-dependent genome folding, following CDC5L depletion. Together, our findings reveal a functional association between RNA-processing factors and cohesin-mediated genome organization, suggesting an additional functional layer that links transcription-associated processes to higher-order chromatin architecture.