Disruption of Nipbl/Scc2 in Cornelia de Lange Syndrome provokes cohesin genome-wide redistribution with an impact in the transcriptome
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ABSTRACT:
PROVIDER: PRJNA608892 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11185427.fastq.gz | Fastqsanger.gz | |||
| SRR11185428.fastq.gz | Fastqsanger.gz | |||
| SRR11185429.fastq.gz | Fastqsanger.gz | |||
| SRR11185430.fastq.gz | Fastqsanger.gz | |||
| SRR11185431.fastq.gz | Fastqsanger.gz |
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Similar Datasets
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: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: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. In this transcriptome analysis, patient derived skin fibroblasts from two CHOPS syndrome probands, two Cornelia de Lange syndrome probands, and four age-gender-ethnicity matched healthy control subjects were used.The samples used for Human Gene 2.0 arrays are two CHOPs syndrome samples (CDL160 and CDL444), two Cornelia de Lange syndrome samples (CdL006: 7 year-old Caucasian female NIPBL 742_743delCT ;L248TfsX6 and CdL015: 10 year-old Caucasian male NIPBL 2969delG;G990DfsX2), and four age gender matched control samples (GM01652, GM01864, GM02036 and GM03348).
2015-01-27 | E-GEOD-64034 | biostudies-arrayexpress
Project description:Cornelia de Lange Syndrome is a multisystem developmental disorder typically caused by mutations in the gene encoding the cohesin loader NIPBL. The associated phenotype is generally assumed to be the consequence of aberrant transcriptional regulation. Recently, we identified a residue substitution in BRD4 associated with a Cornelia de Lange-like Syndrome, that reduces BRD4 binding to acetylated histones. Here we show that, although this mutation reduces BRD4-enhancer interaction in mouse embryonic stem cells, it does not affect transcription. Rather it delays the cell cycle, increased DNA damage signalling, and perturbs regulation of DNA repair in mutant cells. This uncovers a new role for BRD4 in DNA repair pathway choice. Furthermore, we find evidence of a similar increase in DNA damage signalling in cells derived from NIPBL-deficient individuals, suggesting that defective DNA damage signalling and repair is also a feature of typical Cornelia de Lange Syndrome.
2021-03-09 | GSE130659 | GEO
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: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.
| S-EPMC8316422 | biostudies-literature
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:Mutations in NIPBL are the major cause of Cornelia de Lange Syndrome (CdLS). NIPBL is the cohesin loading factor and has recently been associated with the BET (Bromodomains and Extra Terminal (ET) domain) proteins BRD2 and BRD4. Related to this, a CdLS-like phenotype has been described associated to BRD4 mutations. We have study the genomic occupancy of NIPBL in mouse P19 teratocarcinoma cells.
2020-01-01 | GSE132784 | 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