BACKGROUND: Cornelia de Lange syndrome (CdLS) is a multisystem developmental 
disorder frequently associated with heterozygous loss-of-function mutations of 
Nipped-B-like (NIPBL), the human homolog of Drosophila Nipped-B. NIPBL loads 
cohesin onto chromatin. Cohesin mediates sister chromatid cohesion important for 
mitosis but is also increasingly recognized as a regulator of gene expression. 
In CdLS patient cells and animal models, expression changes of multiple genes 
with little or no sister chromatid cohesion defect suggests that disruption of 
gene regulation underlies this disorder. However, the effect of NIPBL 
haploinsufficiency on cohesin binding, and how this relates to the clinical 
presentation of CdLS, has not been fully investigated. Nipbl haploinsufficiency 
causes CdLS-like phenotype in mice. We examined genome-wide cohesin binding and 
its relationship to gene expression using mouse embryonic fibroblasts (MEFs) 
from Nipbl+/- mice that recapitulate the CdLS phenotype.
RESULTS: We found a global decrease in cohesin binding, including at 
CCCTC-binding factor (CTCF) binding sites and repeat regions. Cohesin-bound 
genes were found to be enriched for histone H3 lysine 4 trimethylation (H3K4me3) 
at their promoters; were disproportionately downregulated in Nipbl mutant MEFs; 
and displayed evidence of reduced promoter-enhancer interaction. The results 
suggest that gene activation is the primary cohesin function sensitive to Nipbl 
reduction. Over 50% of significantly dysregulated transcripts in mutant MEFs 
come from cohesin target genes, including genes involved in adipogenesis that 
have been implicated in contributing to the CdLS phenotype.
CONCLUSIONS: Decreased cohesin binding at the gene regions is directly linked to 
disease-specific expression changes. Taken together, our Nipbl 
haploinsufficiency model allows us to analyze the dosage effect of cohesin 
loading on CdLS development.