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MAU2 and NIPBL variants in Cornelia de Lange syndrome reveal MAU2-independent loading of cohesin and uncover protective mechanisms against early truncating mutations in NIPBL

ABSTRACT: For its association with chromatin, the cohesin complex depends on a heterodimer formed by NIPBL and MAU2. Variants in NIPBL are the main cause of CdLS and result in NIPBL haploinsufficiency. Using CRISPR, we generated cells homozygous for an out-of-frame duplication in NIPBL. Remarkably, alternative translation initiation rescued NIPBL expression in these cells and produced an N-terminally truncated NIPBL that lacks MAU2-interaction domain, causing a dramatic reduction of MAU2 protein levels while a lot of NIPBL functions remain intact.

ORGANISM(S): Homo sapiens

PROVIDER: GSE122299 | GEO | 2020/06/10

REPOSITORIES: GEO

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Disruption of Nipbl/Scc2 in Cornelia de Lange Syndrome provokes cohesin genome-wide redistribution with an impact in the transcriptome

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.

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MAU2 and NIPBL variants in Cornelia de Lange syndrome reveal MAU2-independent loading of cohesin and uncover protective mechanisms against early truncating mutations in NIPBL

Project description:MAU2 and NIPBL variants in Cornelia de Lange syndrome reveal MAU2-independent loading of cohesin and uncover protective mechanisms against early truncating mutations in NIPBL

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Impaired Cohesin Loading in Cornelia de Lange Syndrome Results in a Highly Specific Pattern of Dysregulated Genes

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

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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.

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Project description:Cohesinopathies are characterized by mutations in the cohesin complex. Mutations in NIPBL, a cohesin loader, result in Cornelia de Lange syndrome (CdLS). CdLS is a congenital genetic disorder distinguished by craniofacial dysmorphism, abnormal upper limb development, delayed growth, severe cognitive retardation, and multiple organ malformations.It has been suggested that CdLS is caused by defects in the cohesin network that alter gene expression and genome organization. However, the precise molecular etiology of CdLS is largely unclear. To gain insights, we sequenced mRNAs isolated from mouse embryonic fibroblasts of both WT and NIPBL-haploinsufficient mice and compared their transcriptomes.

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Transcriptional dysregulation associated with chromatin accessibility of iPSC and hepatocytes derived from a Cornelia de Lange syndrome patient (WGS)

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