Experimental Immunology Branch, Center for Cancer Research, Bethesda, MD, USA.
Computational Genomics and Bioinformatics Branch, Center for Biomedical Informatics and Information Technology, National Cancer Institute, Bethesda, MD, USA.
Sci Adv. 2023 Mar;9(9):eade3876. doi: 10.1126/sciadv.ade3876. Epub 2023 Mar 1.
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.
黏连蛋白是一种三聚体复合物，可建立姐妹染色单体黏合，在染色质组织和转录中具有额外的作用。我们报告称，在这些作用中，通过与剪接因子的直接相互作用和原位共定位，调节选择性剪接。黏连蛋白的降解导致剪接发生明显变化，这与其对转录的影响无关。在胚胎干细胞中引入单个黏连蛋白点突变会改变剪接模式，证明了因果关系。在原发性人类急性髓性白血病中，黏连蛋白的突变与明显不同的选择性剪接模式高度相关。黏连蛋白还与另一个剪接调节因子 BRD4 直接相互作用，产生一种与任何一个因子都不同的剪接模式，证明了它们的功能相互作用。这些发现确定了黏连蛋白在正常和白血病细胞中调节选择性剪接的作用，并为人类疾病中黏连蛋白突变的作用提供了新的见解。
