Genome wide DNA Methylation Study in Cornelia de Lange Syndrome
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE18458 | GEO | 2010/07/07
SECONDARY ACCESSION(S): PRJNA118177
REPOSITORIES: GEO
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Project description:Differential DNA methylation was identified in CdLS, and correlates to cohesin binding as well. However, DNA methylation may only be one of several events that regulate gene expression in humans. 63 Lymphoblastoid cell lines (LCLs) from 39 CdLS probands, 2 RBS probands and 22 gender and racial matched healthy controls were tested on HumanMethylation27 DNA Analysis BeadChip (Illumina) which carries 27,578 highly informative CpG sites derived from the well-annotated NCBI CCDS database
2010-07-07 | E-GEOD-18458 | biostudies-arrayexpress
Project description:Cornelia de Lange syndrome (CdLS) is a complex multisystem developmental disorder caused by mutations in cohesin subunits and regulators. While the precise molecular mechanisms are not well defined, they point toward a global deregulation of the transcriptional gene expression program. Indeed, cohesin is associated with the boundaries of chromosome domains in addition to enhancers and promoters connecting the 3D genome organization with transcriptional control and gene expression. Here we show that connected gene communities, built with noncoding regulatory elements and genes physically interacting in the 3D chromosomal space, provide a molecular explanation for the pathoetiology of CdLS. Indeed, NIPBL and cohesin are important constituents of connected gene communities, both being centrally positioned at active noncoding regulatory elements. Interestingly, mutations in SMC1A and NIPBL lead to coordinated gene expression changes in connected communities. Our findings suggest a model where CdLS is explained by coordinated modulation of connected gene communities.
2017-07-13 | GSE93080 | GEO
Project description:Heterozygous mutations in the cohesin regulator, NIPBL, or cohesin structural components SMC1A, and SMC3, result in Cornelia de Lange Syndrome (CdLS). Genome-wide transcription assessment has identified unique profiles of genes dysregulated in CdLS that correlate with different clinical presentations. Cohesin binding analysis demonstrates a preference for intergenic regions suggesting a cis-regulatory function mimicking that of an insulator. However, the binding sites are enriched within the promoter regions of the dysregulated genes and are significantly decreased in CdLS probands, indicating an alternative role of cohesin as a classic transcription factor. Keywords: ChIP-chip
2009-05-28 | GSE12603 | GEO
Project description: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 mechanism driving the CdLS phenotypes are not understood. Apart from its canonical role in sister chromatid cohesion, cohesin has also been involved in the regulation of the spatial organization of the genome. Here, we investigated the transcriptome of CdLS-derived primary fibroblasts (gene expression microarray data included in the manuscript as an excel file) and observed the downregulation of genes involved in development and system skeletal organization providing a link to the developmental alterations and limb abnormalities characteristics of the CdLS patients. Genome-wide distribution studies demonstrated 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 probably due to reduced cohesin translocation along chromosomes and fewer cohesin peaks colocalize with CTCF.
2021-05-27 | GSE145966 | GEO
Project description:The cohesin protein complex is essential for the formation of topologically associating domains (TADs) and chromatin loops on interphase chromosomes. For the loading onto chromosomes, cohesin requires the cohesin loader complex formed by NIPBL and MAU2. Cohesin localizes at enhancers and gene promoters with NIPBL in mammalian cells and forms enhancer-promoter loops. Cornelia de Lange syndrome (CdLS) is a rare, genetically heterogeneous disorder affecting multiple organs and systems during development, caused by mutations in the cohesin loader NIPBL gene (> 60% of patients), as well as in genes encoding cohesin, a chromatin regulator, BRD4, and cohesin-related factors. We also reported CHOPS syndrome that phenotypically overlaps with CdLS and is caused by gene mutations of a super elongation complex (SEC) core component, AFF4. Although these syndromes are associated with transcriptional dysregulation, the underlying mechanism remains unclear. In this study, we provide the first comprehensive analysis of chromosome architectural changes caused by these mutations using cell lines derived from CdLS and CHOPS syndrome patients. In both patient cells, we found a decrease in cohesin, NIPBL, BRD4, and acetylation of lysine 27 on histone H3 (H3K27ac) in most enhancers with enhancer-promoter loop attenuation. In contrast, TADs were maintained in both patient cells. These findings reveal a shared molecular mechanism in these syndromes and highlight unexpected roles for cohesin, cohesin loaders, and the SEC in maintaining the enhancer complexes. These complexes are crucial for recruiting transcriptional regulators, sustaining active histone modifications, and facilitating enhancer-promoter looping.
2025-02-21 | GSE277780 | GEO
Project description:The cohesin protein complex is essential for the formation of topologically associating domains (TADs) and chromatin loops on interphase chromosomes. For the loading onto chromosomes, cohesin requires the cohesin loader complex formed by NIPBL and MAU2. Cohesin localizes at enhancers and gene promoters with NIPBL in mammalian cells and forms enhancer-promoter loops. Cornelia de Lange syndrome (CdLS) is a rare, genetically heterogeneous disorder affecting multiple organs and systems during development, caused by mutations in the cohesin loader NIPBL gene (> 60% of patients), as well as in genes encoding cohesin, a chromatin regulator, BRD4, and cohesin-related factors. We also reported CHOPS syndrome that phenotypically overlaps with CdLS and is caused by gene mutations of a super elongation complex (SEC) core component, AFF4. Although these syndromes are associated with transcriptional dysregulation, the underlying mechanism remains unclear. In this study, we provide the first comprehensive analysis of chromosome architectural changes caused by these mutations using cell lines derived from CdLS and CHOPS syndrome patients. In both patient cells, we found a decrease in cohesin, NIPBL, BRD4, and acetylation of lysine 27 on histone H3 (H3K27ac) in most enhancers with enhancer-promoter loop attenuation. In contrast, TADs were maintained in both patient cells. These findings reveal a shared molecular mechanism in these syndromes and highlight unexpected roles for cohesin, cohesin loaders, and the SEC in maintaining the enhancer complexes. These complexes are crucial for recruiting transcriptional regulators, sustaining active histone modifications, and facilitating enhancer-promoter looping.
2025-02-21 | GSE277779 | GEO
Project description:CdLS is caused by mutaion in cohesin and associated proteins, such as Nipbl and Hdac8. We performed RNA seq analysis from Nipbl+/- and Hdac8-/0 placenta with their respective wild type control at 14.5 dpc, to identify molecular pathways affected. To understand the effect of protein kinase R (PKR) on gene expression we also performed RNA seq analysis from Nipbl+/- and Hdac8-/0 placenta lacking PKR.
2020-07-27 | GSE138687 | GEO
Project description:The Cohesin apparatus has a canonical role in sister chromatid cohesion. Heterozygous mutations in Nipped B-like (NIPBL), SMC1A, and SMC3 have been found in 60% of probands with Cornelia de Lange Syndrome (CdLS), a dominant multi-system genetic disorder with variable expression. We have performed a genome-wide transcription assessment as well as cohesin binding analysis using human lymphoblastoid cell lines (LCLs) from probands with CdLS and controls. Here, we report a unique profile of genes dysregulated in CdLS that correlates with different clinical presentations. Genome-wide analysis of cohesin binding demonstrates a preference for intergenic regions suggesting a cis-regulatory function mimicking that of an insulator. However, the binding sites are enriched within the promoter regions of the dysregulated genes and are significantly decreased in CdLS probands, indicating an alternative role of cohesin as a classic transcription factor. Cohesin also co-localizes with CTCF at the boundary elements affecting neighboring gene expression in CdLS probands. We propose that the CdLS phenotype is the result of dysregulated gene expression rather than defective sister chromatid cohesion. Phenotype specific expression profiles are also described. Experiment Overall Design: To identify differentially expressed genes between CdLS patients and controls, age and gender matched samples from 16 normal Caucasian controls and 17 clinical severely affected Caucasian patients with NIPBL protein truncating mutations (nonsense or frameshift) were chosen as the training set for the discriminate analysis. To validate the expression pattern obtained from the training set, 6 samples including 1 healthy control, 1 Egyptian CdLS patient, 2 Roberts syndrome patients, and 2 Alagille patients were used as the testing set. All the 39 cell lines were growing anonymously and the processing of these 39 cell lines were randomized by genotypes to eliminate batch effects that may contribute to genotype-specific gene expression
2009-06-08 | E-GEOD-12408 | biostudies-arrayexpress
Project description:CHOPS syndrome is caused by germline gain-of-function mutations of AFF4. Cornelia de Lange syndrome is caused by germline mutations of cohesin loading factors or cohesin complex genes such as NIPBL, SMC1A, SMC3 and HDAC8. There are many overlapping clinical features exist between CHOPS syndrome and Cornelia de Lange syndrome. To identified commonly dysregulated genes in CHOPS syndrome and Cornelia de Lange syndrome, we perfomred side-by-side transcriptome comparison between CHOPS syndrome and Cornelia de Lange syndrome.
2015-01-27 | GSE64034 | GEO
Project description:Cornelia de Lange syndrome (CdLS) is an autosomal dominant disease mainly caused by mutations in the Nipped-B-like protein (NIPBL) gene resulting in the alteration of the cohesin pathway. Here, we generated human induced pluripotent stem cells (hiPSCs) from a CdLS patient carrying a mutation in the NIPBL gene, c.5483G>A, and tested CRISPR-Cas based approaches to repair the genetic defect. We applied an efficient and precise method of gene correction through CRISPR-Cas induced homology directed repair (HDR), which allowed the generation of hiPSC clones with regular karyotype and preserved stemness. The efficient and precise gene replacement strategy developed in this study can be extended to the modification of other genomic loci in hiPSCs. Isogenic wild-type and mutated hiPSCs produced with the CRISPR-Cas technology are fundamental CdLS cellular models to study the disease molecular determinants and identifying therapeutic targets.
2023-03-17 | E-MTAB-11604 | biostudies-arrayexpress