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

ABSTRACT: Interphase cohesin organizes the genome into loops and domains, yet how cohesin is efficiently recruited and loaded onto chromatin in cells remains incompletely understood. 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE338182 | GEO | 2026/08/27

REPOSITORIES: GEO

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Project description:In this study we combined selective labelling and acute depletion of mitotic inherited cohesin during the telophase-G1 passage to interrogate the functional relevance of cohesin on post-mitotic transcriptional reactivation. Our results tracking pre-mitotic labelled cohesin demonstrate transmission of both cohesinSTAG1 and cohesinSTAG2 complexes through mitosis, the first one showing faster reassociation with chromatin. Nipbl and Wapl, although using opposite mechanisms, both play an essential role on cohesin inheritance and reuse. Remarkably, our labelling strategy allowed us to differentially mark and track mitotic-inherited and new-translated cohesin. Our findings demonstrate that the large fraction of functional-chromatin bound cohesin early in G1 corresponds to the mitotic-transmitted fraction. This pool is sequentially displaced by new-translated cohesin at the G1-S transition. Our results reveal that recycled cohesin preferentially localizes to active chromatin, especially promoters, enhancers, and CTCF sites, and that this enrichment partially relies on the bookmarking factor TBP. Nascent transcriptomic analysis under acute depletion of Rad21 reveal cohesin-dependent transcriptional regulation of hundreds of genes enriched on tissue growth and development categories. We observed selective disruption of phosphor-ser2 RNAPol2 variant under Rad21 depletion in down-regulated genes, which support that cohesin facilitates promoter-paused to active-elongating RNAPol2 transition. Indeed, our results reveal Rad21-Cdk9 direct interaction and that Rad21/cohesinSTAG1 ensures proper Cdk9 function/chromatin levels early in G1. Overall, our findings support a mechanism based on the direct interaction of mitotic-inherited cohesin with the promoter of a specific set of genes to facilitate Cdk9-mediated activation of RNAPol2. In conclusion, our findings evidence that the mitotic transmission of cohesin ensures full post-mitotic transcriptional recovery and, importantly, reveal a locus-specific mechanism linking cohesin to RNAPol2 activation.

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

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