Transcriptional dysregulation in NIPBL and cohesin mutant human cells.
Transcriptional dysregulation in NIPBL and cohesin mutant human cells.
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DOI：
10.1371/journal.pbio.1000119
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发表时间：
2009-05-05
期刊：
影响因子：
9.8
通讯作者：
Krantz ID
中科院分区：
文献类型：
--
作者：
Liu J;Zhang Z;Bando M;Itoh T;Deardorff MA;Clark D;Kaur M;Tandy S;Kondoh T;Rappaport E;Spinner NB;Vega H;Jackson LG;Shirahige K;Krantz ID
使用Cornelia de Lange综合征患者的细胞进行的全基因组研究揭示了粘附素在调节人类细胞基因表达方面的作用。在有丝分裂细胞周期中，粘附素调节姐妹染色单体的凝聚力，并通过NIPBL促进其加载和卸载。除了这种典型的作用外，粘附素还被证明在未分裂细胞的基因表达调控中发挥关键作用。粘附素调节基因NIPBL或粘附素结构成分SMC1a和SMC3的杂合突变导致多系统发育障碍Cornelia de Lange综合征(CDLS)。对来自受严重影响的CDLS先证者的16个突变细胞系的全基因组转录评估发现了一个独特的失调基因表达谱，该谱在另外101个样本中得到验证，并与表型严重程度相关。这份档案可以作为诊断和分类工具。粘附素结合分析显示偏爱基因间隔区，提示顺式调节功能模仿边界/绝缘子相互作用蛋白的顺式调节功能。然而，结合位点在异常基因的启动子区域内丰富，而在CDLS先证者中显著减少，表明粘附素作为转录因子具有替代作用。染色体到子代细胞的适当分离取决于有丝分裂过程中姐妹染色单体的适当凝聚。多蛋白粘附素复合体及其调控因子是这一过程中的关键因素。有趣的是，最近的研究表明，粘附素复合体还具有其他细胞功能，包括调节基因表达的作用。此外，粘附素结构和调节成分的突变与人类多系统发育障碍有关，如Cornelia de Lange综合征(CDLS)，但粘附素在这种疾病的发病机制中所起的作用尚不清楚。为了确定粘附素在调节人类细胞基因表达中所起的作用，我们分析了正常受试者和粘附素调节因子NIPBL或粘附素结构成分SMC1A突变的CDLS先证者细胞中的基因表达和全基因组粘附素结合模式。我们在这些不同的细胞系中发现了一种非常保守的基因失调模式，这种模式与疾病的严重程度相关，并且基因失调与错误表达基因周围的粘附素结合之间存在显着的相关性。观察到的结合和错误表达的模式与粘附素作为边界/绝缘体相互作用蛋白或转录因子的推测一致，其活性在CDLS先证者中被破坏。
Genome-wide studies using cells from patients with Cornelia de Lange Syndrome reveal a role for cohesin in regulating gene expression in human cells. Cohesin regulates sister chromatid cohesion during the mitotic cell cycle with Nipped-B-Like (NIPBL) facilitating its loading and unloading. In addition to this canonical role, cohesin has also been demonstrated to play a critical role in regulation of gene expression in nondividing cells. Heterozygous mutations in the cohesin regulator NIPBL or cohesin structural components SMC1A and SMC3 result in the multisystem developmental disorder Cornelia de Lange Syndrome (CdLS). Genome-wide assessment of transcription in 16 mutant cell lines from severely affected CdLS probands has identified a unique profile of dysregulated gene expression that was validated in an additional 101 samples and correlates with phenotypic severity. This profile could serve as a diagnostic and classification tool. Cohesin binding analysis demonstrates a preference for intergenic regions suggesting a cis-regulatory function mimicking that of a boundary/insulator interacting protein. However, the binding sites are enriched within the promoter regions of the dysregulated genes and are significantly decreased in CdLS proband, indicating an alternative role of cohesin as a transcription factor. Appropriate segregation of chromosomes to daughter cells depends upon proper cohesion of sister chromatids during mitosis. The multiprotein cohesin complex and its regulators are key factors in this process. Intriguingly, recent work has shown that the cohesin complex also has other cellular roles, including a role in regulating gene expression. Additionally, mutations in cohesin structural and regulatory components have been linked to human multisystem developmental disorders such as Cornelia de Lange Syndrome (CdLS), but the role cohesin is playing in the pathogenesis of this disorder is unknown. To define the role that cohesin plays in regulating gene expression in human cells, we analyzed gene expression and genome-wide cohesin binding patterns in cells from normal subjects and from CdLS probands with mutations in the cohesin regulator NIPBL or in the cohesin structural component SMC1A. We found a strikingly conserved pattern of gene dysregulation in these different cell lines that correlates with disease severity and a significant correlation between gene dysregulation and cohesin binding around misexpressed genes. The observed pattern of binding and misexpression is consistent with cohesin having a putative role as a boundary/insulator interacting protein or transcription factor, the activity of which is disrupted in CdLS probands.
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影响因子：
3.7
作者：
Díaz-Martínez LA;Giménez-Abián JF;Azuma Y;Guacci V;Giménez-Martín G;Lanier LM;Clarke DJ
通讯作者：
Clarke DJ
影响因子：
64.8
作者：
Arron, Joseph R.;Winslow, Monte M.;Crabtree, Gerald R.
通讯作者：
Crabtree, Gerald R.
影响因子：
16
作者：
Haering, CH;Löwe, J;Nasmyth, K
通讯作者：
Nasmyth, K
影响因子：
16
作者：
Haering, CH;Schoffnegger, D;Löwe, J
通讯作者：
Löwe, J
影响因子：
10.5
作者：
Chang, CR;Wu, CS;Gartenberg, MR
通讯作者：
Gartenberg, MR