Cohesin Regulates Alternative Splicing in Acute Myeloid Leukemia

Authors

• S Porche
• JC Nelson
• S Moir
• H Kalish

Abstract

Cohesin is a ring-shaped complex with multiple functions throughout cell cycle. Cohesin establishes sister-chromatid cohesion, organizes chromatin into functional domains, regulates transcription and DNA repair. The high frequency of cohesin mutations and of changes in alternative splicing in acute myeloid leukemia (AML) led us to ask if cohesin regulates alternative splicing. Targeted depletion of cohesin in HCT-116 cells led to changes in splicing patterns, demonstrating that cohesin regulates alternative splicing. Mechanistically, cohesin colocalizes and directly interacts with core components of splicing machinery including U1-70, and regulatory factor FUS. Acute cohesin depletion did not affect mRNA levels, rate of transcription and splicing factor levels. Furthermore, in two independent datasets, primary AML patient samples with cohesin mutations show aberrant splicing patterns relative to healthy controls. Importantly, cohesin point mutations observed in AML samples display reduced in-vitro interactions with U1-70. Introduction of a point mutation in the SMC1 subunit in mES cells reduces the in-situ proximity of cohesin with U1-70 and alters splicing patterns. This finding demonstrates a direct relationship between cohesin and splicing. BRD4, like cohesin, regulates alternative splicing. Interestingly, cohesin and BRD4 together regulate the splicing of a gene subset that is distinct from those regulated by either protein alone. Consistent with their co-regulation of splicing, cohesin and BRD4 colocalize across the genome, directly interact and exist in a complex in cells. Together these studies establish a novel role of cohesin in regulating alternative splicing alone or in conjunction with BRD4 and have implications in the characterization of human AML cancers.

Scientific Focus Area: Molecular Biology and Biochemistry

This page was last updated on Monday, September 25, 2023