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Cohesin mediates transcriptional insulation by CCCTC-binding factor

ABSTRACT: Chromosome segregation in mitosis and meiosis depends on sister chromatid cohesion mediated by cohesin complexes. Mutation of cohesin and other cohesion proteins causes transcriptional and developmental defects in animals and humans, but the molecular cause of these phenotypes is unknown. Here we describe 8811 cohesin binding sites in the human genome and show that the CCCTC-binding factor (CTCF) is associated with 88% of these. CTCF is dispensable for loading of cohesin onto DNA but is required for enrichment of cohesin at its binding sites. We provide evidence that cohesin is required for the role of CTCF sites in insulating promoters from distant enhancers. Like CTCF, cohesin is located on the maternal but not on the paternal allele of the H19 imprinting control region (ICR) and is required for imprinting of the H19-Igf2 locus. We find that cohesin is widely expressed in mammalian tissues, consistent with a cohesionindependent role in regulating gene expression. We propose that cohesin functions as a transcriptional insulator and speculate that subtle deficiencies in this function may be the cause of "cohesinopathies" such as Cornelia de Lange and Roberts syndrome. Keywords: ChIP-chip analysis

ORGANISM(S): Homo sapiens

PROVIDER: GSE9613 | GEO | 2008/01/30

SECONDARY ACCESSION(S): PRJNA103467

REPOSITORIES: GEO

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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

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Cohesin mediates transcriptional insulation by CCCTC-binding factor

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