Cohesin regulates alternative splicing

Abstract

Cohesin, a trimeric complex that establishes sister chromatid cohesion, has additional roles in chromatin organization 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 leukemia, 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 regulating alternative splicing in both normal and leukemic cells and provide insights into the role of cohesin mutations in human disease.

Synaptonemal Complex in Human Biology and Disease

“…Furthermore, recent studies have identified genetic variants of the other meiotic-specific cohesins SMC1β, REC8, and RAD21L associated with infertility phenotypes including POI and NOA [ 76 , 79 , 80 , 81 , 82 ]. Moreover, the recent discovery of cohesin involvement in RNA splicing can provide a potential avenue for investigating the etiology of idiopathic infertility, in which non-null hypomorphic mutations in meiotic cohesins may be disrupting the transcriptional program of gametogenesis [ 83 ].…”