Cohesin regulates alternative splicing

Cohesin, a trimeric complex that establishes sister chromatid cohesion, has additional roles in chromatin orga-nization and transcription. We report that among those roles is the regulation of alternative splicing through direct interactions and in situ colocalization with splicing factors. Degradation of cohesin results in marked changes in splicing, independent of its effects on transcription. Introduction of a single cohesin point mutation in embryonic stem cells alters splicing patterns, demonstrating causality. In primary human acute myeloid leu-kemia, mutations in cohesin are highly correlated with distinct patterns of alternative splicing. Cohesin also directly interacts with BRD4, another splicing regulator, to generate a pattern of splicing that is distinct from either factor alone, documenting their functional interaction. These findings identify a role for cohesin in reg-ulating alternative splicing in both normal and leukemic cells and provide insights into the role of cohesin mu-tations in human disease.