Cancer Epigenetics Training Program, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
Integrative Program for Biological and Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
PLoS Genet. 2021 Mar 24;17(3):e1009435. doi: 10.1371/journal.pgen.1009435. eCollection 2021 Mar.
The cohesin complex spatially organizes interphase chromatin by bringing distal genomic loci into close physical proximity, looping out the intervening DNA. Mutation of cohesin complex subunits is observed in cancer and developmental disorders, but the mechanisms through which these mutations may contribute to disease remain poorly understood. Here, we investigate a recurrent missense mutation to the hinge domain of the cohesin subunit SMC1A, observed in acute myeloid leukemia. Engineering this mutation into murine embryonic stem cells caused widespread changes in gene expression, including dysregulation of the pluripotency gene expression program. This mutation reduced cohesin levels at promoters and enhancers, decreased DNA loops and interactions across short genomic distances, and weakened insulation at CTCF-mediated DNA loops. These findings provide insight into how altered cohesin function contributes to disease and identify a requirement for the cohesin hinge domain in three-dimensional chromatin structure.
黏合蛋白复合物通过将远端基因组区域拉近到紧密的物理距离，将染色质在空间上组织起来，形成环，从而将 intervening DNA 环出。黏合蛋白复合物亚基的突变在癌症和发育障碍中被观察到，但这些突变如何导致疾病的机制仍知之甚少。在这里，我们研究了在急性髓性白血病中观察到的黏合蛋白亚基 SMC1A 铰链结构域的一种复发性错义突变。将这种突变引入到小鼠胚胎干细胞中，导致了广泛的基因表达变化，包括多能性基因表达程序的失调。这种突变降低了启动子和增强子处的黏合蛋白水平，减少了短基因组距离上的 DNA 环和相互作用，并削弱了 CTCF 介导的 DNA 环的绝缘性。这些发现为了解黏合蛋白功能的改变如何导致疾病提供了线索，并确定了黏合蛋白铰链结构域在三维染色质结构中的必要性。
