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A common molecular mechanism underlying Cornelia de Lange and CHOPS syndromes

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE277780 | GEO | 2025/02/21

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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A common molecular mechanism underlying Cornelia de Lange and CHOPS syndromes

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