Disruption of NIPBL/Scc2 in Cornelia de Lange Syndrome provokes cohesin genome-wide redistribution with an impact in the transcriptome.
Disruption of NIPBL/Scc2 in Cornelia de Lange Syndrome provokes cohesin genome-wide redistribution with an impact in the transcriptome.
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DOI：
10.1038/s41467-021-24808-z
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发表时间：
2021-07-27
影响因子：
16.6
通讯作者：
Queralt E
中科院分区：
文献类型：
--
作者：
Garcia P;Fernandez-Hernandez R;Cuadrado A;Coca I;Gomez A;Maqueda M;Latorre-Pellicer A;Puisac B;Ramos FJ;Sandoval J;Esteller M;Mosquera JL;Rodriguez J;Pié J;Losada A;Queralt E
科尔内利亚德兰格综合征（CdLS）是一种罕见的疾病，影响多个器官和系统的发展。首先描述了粘附素装载器NIPBL/Scc 2中的突变，并且在临床诊断的CdLS患者中最常见。驱动CdLS表型的分子机制尚不清楚。除了其在姐妹染色单体凝聚中的典型作用外，凝聚素还涉及基因组的空间组织。在这里，我们研究了CdLS患者来源的原代成纤维细胞的转录组，并观察了参与发育和系统骨骼组织的基因的下调，为CdLS患者的发育改变和肢体异常特征提供了联系。全基因组分布研究表明，在CdLS衍生的细胞中，NIPBL相关的高GC含量区域的NIPBL整体减少。此外，可能由于沿染色体的粘附素易位沿着减少，粘附素在CpG岛的NIPBL占据位点处积累，并且较少的粘附素峰与CTCF共定位。患有科尔内利亚德兰格综合征（CdLS）的患者通常具有粘附素及其调节剂的突变;然而，驱动CdLS表型的分子机制尚未完全建立。在这里，作者揭示了系统骨骼组织基因的下调，并表明粘附素及其装载者Nipbl改变和减少了全基因组定位。
Cornelia de Lange syndrome (CdLS) is a rare disease affecting multiple organs and systems during development. Mutations in the cohesin loader, NIPBL/Scc2, were first described and are the most frequent in clinically diagnosed CdLS patients. The molecular mechanisms driving CdLS phenotypes are not understood. In addition to its canonical role in sister chromatid cohesion, cohesin is implicated in the spatial organization of the genome. Here, we investigate the transcriptome of CdLS patient-derived primary fibroblasts and observe the downregulation of genes involved in development and system skeletal organization, providing a link to the developmental alterations and limb abnormalities characteristic of CdLS patients. Genome-wide distribution studies demonstrate a global reduction of NIPBL at the NIPBL-associated high GC content regions in CdLS-derived cells. In addition, cohesin accumulates at NIPBL-occupied sites at CpG islands potentially due to reduced cohesin translocation along chromosomes, and fewer cohesin peaks colocalize with CTCF. Patients with Cornelia de Lange Syndrome (CdLS) often have mutations in cohesin and its regulators; however, the molecular mechanism driving CdLS phenotypes is not well established. Here the authors reveal system skeletal organization genes are downregulated and show that cohesin and its loader Nipbl have altered and decreased genome-wide localization.
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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
影响因子：
4
作者：
Ansari M;Poke G;Ferry Q;Williamson K;Aldridge R;Meynert AM;Bengani H;Chan CY;Kayserili H;Avci S;Hennekam RC;Lampe AK;Redeker E;Homfray T;Ross A;Falkenberg Smeland M;Mansour S;Parker MJ;Cook JA;Splitt M;Fisher RB;Fryer A;Magee AC;Wilkie A;Barnicoat A;Brady AF;Cooper NS;Mercer C;Deshpande C;Bennett CP;Pilz DT;Ruddy D;Cilliers D;Johnson DS;Josifova D;Rosser E;Thompson EM;Wakeling E;Kinning E;Stewart F;Flinter F;Girisha KM;Cox H;Firth HV;Kingston H;Wee JS;Hurst JA;Clayton-Smith J;Tolmie J;Vogt J;Tatton-Brown K;Chandler K;Prescott K;Wilson L;Behnam M;McEntagart M;Davidson R;Lynch SA;Sisodiya S;Mehta SG;McKee SA;Mohammed S;Holden S;Park SM;Holder SE;Harrison V;McConnell V;Lam WK;Green AJ;Donnai D;Bitner-Glindzicz M;Donnelly DE;Nellåker C;Taylor MS;FitzPatrick DR
通讯作者：
FitzPatrick DR
影响因子：
9.2
作者：
Gerlich, Daniel;Koch, Birgit;Ellenberg, Jan
通讯作者：
Ellenberg, Jan
影响因子：
11.4
作者：
Carretero, Maria;Ruiz-Torres, Miguel;Losada, Ana
通讯作者：
Losada, Ana
影响因子：
64.8
作者：
Hadjur, Suzana;Williams, Luke M.;Ryan, Natalie K.;Cobb, Bradley S.;Sexton, Tom;Fraser, Peter;Fisher, Amanda G.;Merkenschlager, Matthias
通讯作者：
Merkenschlager, Matthias