Nipbl haploinsufficiency in Cornelia de Lange Syndrome

University Of California-Irvine, Irvine CA

Investigators

Abstract

DESCRIPTION (provided by applicant): Cornelia de Lange Syndrome (CdLS) is an autosomal dominant multisystem developmental disorder characterized by facial dysmorphism, hirsutism, upper limb abnormalities, cognitive retardation, and growth abnormalities. Over 50% of cases are associated with mutations in the NIPBL gene resulting in NIPBL haploinsufficiency. NIPBL (Nipbl in mice) is required for loading of the essential multiprotein complex cohesin onto chromatin. Cohesin functions in sister chromatid cohesion important for mitosis and DNA repair as well as in developmental gene regulation. Nipbl haploinsufficiency causes reduction of cohesin binding to chromatin, which is not sufficiently severe to disrupt sister chromatid cohesion, but does compromise long- range chromatin interactions resulting in alteration of gene expression. It is thought that the Nipbl deficiency generates the clinical features of the disorder primarily through reduced cohesin loading onto chromatin. However, how Nipbl determines the specific loading sites for cohesin in developmental gene regulation and whether it has any additional functions in the cell have not been investigated. We found that Nipbl localizes to the nucleolus and affects ribosomal RNA (rRNA) biosynthesis. Abnormalities in nucleolar function and ribosome biogenesis are known to cause phenotypically similar human developmental disorders with growth and mental retardation, and are thus termed ribosomopathies. It is possible therefore that CdLS is also a ribosomopathy. Importantly, we obtained evidence that Nipbl is an RNA-binding protein and that it associates with the ribosomal DNA (rDNA) region in an RNA-dependent manner. This suggests that RNA is an important mediator of Nipbl function, which may represent a cohesin-independent function and/or may contribute to determining the specificity of cohesin binding to particular genomic regions. Thus, we plan to characterize the RNA-binding activity and nucleolar function of Nipbl and examine their significance in relationship to cohesin function and CdLS pathogenesis, using both human cells and a Nipbl+/- mouse model. The goal of the project is to better understand the CdLS disease mechanism in order to develop a rational approach to potential therapeutic interventions.