부산대학교 도서관

Cornelia de Lange Syndrome (CdLS) is a severe developmentaldisorder frequently associated with heterozygous loss-of-functionNIPBL mutations. NIPBL loads cohesin onto chromatin. Cohesinmediates sister chromatid cohesion important for mitosis, but isalso increasingly being recognized as a regulator of gene expression.In CdLS patient cells and animal models, the presence of multiplegene expression changes with little or no cohesion defect suggeststhat disruption of gene regulation underlies this disorder. However,the effect of NIP BL haploinsufficiency on cohesin binding, and howthis relates .to the clinical presentation of CdLS, has not been fullyinvestigated. We examined genome-wide cohesin binding and itsrelationship to gene expression using mouse embryonic fibroblasts(MEFs) from Nipbl +I- mice that recapitulate the CdLS phenotype.We found a global decrease in cohesin binding, includingthose at CTCF sites and repeat regions. Cohesin-bound genes areenriched for H3K4me3 at the promoters and are mostly downregulatedin Nipbl mutant MEFs with evidence for reduced promoter-enhancer interaction, suggesting that gene activation is theprimary co he sin function sensitive to Nip bl reduction. Over 50% ofgenes affected in mutant MEFs are cohesin target genes, includingthose involved in adipogenesis, indicating their direct contributionsto the Nipbl haploinsufficiency-induced CdLS phenotype.Interestingly, mutations in several cohesin subunit genes exhibitmild and somewhat distinct phenotypes compared to that of NIP BLhaploinsufficiency, raising the possibility that NIPBL may haveunique functions independent of cohesin. We will discuss ourrecent findings that su11port the notion that the cohesin-independentrole ofNIPBL also contributes to the CdLS pathogenesis. Thiswork was supported in part by NIH grants P01-HD052860 and R21HD062951.