A cohesin cancer mutation reveals a role for the hinge domain in genome organization and gene expression.
A cohesin cancer mutation reveals a role for the hinge domain in genome organization and gene expression.
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一种粘着蛋白癌症突变揭示了铰链结构域在基因组组织和基因表达中的作用。
DOI：
10.1371/journal.pgen.1009435
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发表时间：
2021-03
期刊：
影响因子：
4.5
通讯作者：
Dowen JM
中科院分区：
文献类型：
--
作者：
Carico ZM;Stefan HC;Justice M;Yimit A;Dowen JM
粘着蛋白复合物通过使远端基因组位点在物理上紧密接近，从而在空间上组织间期染色质，从而使插入的DNA成环。在癌症和发育障碍中观察到粘着蛋白复合物亚基的突变，但这些突变可能导致疾病的机制仍然知之甚少。在这里，我们调查了在急性髓系白血病中观察到的粘附素亚基SMC1A铰链结构域的复发性错义突变。将这种突变工程化到小鼠胚胎干细胞中引起了基因表达的广泛变化，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的粘附素水平，减少了DNA环和短基因组距离的相互作用，并削弱了CTCF介导的DNA环的绝缘。这些发现提供了深入了解改变的粘附素功能如何有助于疾病，并确定三维染色质结构中的粘附素铰链结构域的要求。哺乳动物基因组由数米长的DNA组成，这些DNA必须高度折叠才能装入细胞核。这种折叠在多个尺度上由不同的生物学机制调节。基因组的空间组织与其功能密切相关，包括基因的时空表达。对基因控制特别重要的是染色体分成DNA环，当两个远端基因座紧密接触时形成DNA环。基因组折叠成DNA环是由粘附素和CTCF完成的。DNA环如何在基因控制中动态形成和发挥作用的分子基础知之甚少。在这里，我们调查了一个复发性癌症突变的cohesin，并表明它会导致改变折叠的基因组DNA环和许多基因的错误表达。这一发现很重要，因为粘附素突变在许多癌症中很常见，但对粘附素缺陷如何导致疾病的了解甚少。
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. Mammalian genomes consist of multiple meters of DNA which must be highly folded in order to fit inside of the nucleus. This folding is regulated at multiple scales by different biological mechanisms. The spatial organization of the genome is closely linked to its function, including the spatial and temporal expression of genes. Especially important for gene control is the partitioning of chromosomes into DNA loops, which are formed when two distal loci are brought into close contact. The folding of the genome into DNA loops is performed by cohesin and CTCF. The molecular basis for how DNA loops dynamically form and function in gene control is poorly understood. Here, we investigate a recurrent cancer mutation in cohesin and show that it causes altered folding of the genome into DNA loops and misexpression of many genes. This finding is important because cohesin mutations are common in many cancers and yet there is little understanding of how cohesin defects may contribute to disease.
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影响因子：
64.5
作者：
Haarhuis JHI;van der Weide RH;Blomen VA;Yáñez-Cuna JO;Amendola M;van Ruiten MS;Krijger PHL;Teunissen H;Medema RH;van Steensel B;Brummelkamp TR;de Wit E;Rowland BD
通讯作者：
Rowland BD
DOI：
10.1016/j.bbcan.2016.05.002
发表时间：
2016-08
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Hill VK;Kim JS;Waldman T
通讯作者：
Waldman T
影响因子：
64.5
作者：
Dowen JM;Fan ZP;Hnisz D;Ren G;Abraham BJ;Zhang LN;Weintraub AS;Schujiers J;Lee TI;Zhao K;Young RA
通讯作者：
Young RA
影响因子：
5.9
作者：
Dowen, Jill M.;Bilodeau, Steve;Young, Richard A.
通讯作者：
Young, Richard A.
影响因子：
16
作者：
Haering, CH;Löwe, J;Nasmyth, K
通讯作者：
Nasmyth, K