Nipbl and Mediator Cooperatively Regulate Gene Expression to Control Limb Development

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Limb malformations are a striking feature of Cornelia de Lange Syndrome (CdLS), a multi-system birth defects disorder most commonly caused by haploinsufficiency for NIPBL. In addition to its role as a cohesin-loading factor, Nipbl also regulates gene expression, but how partial Nipbl deficiency causes limb defects is unknown. Using zebrafish and mouse models, we show that expression of multiple key regulators of early limb development, including shha, hand2 and hox genes, are sensitive to Nipbl deficiency. Furthermore, we find morphological and gene expression abnormalities similar to those of Nipbl-deficient zebrafish in the limb buds of zebrafish deficient for the Med12 subunit of Mediator—a protein complex that mediates physical interactions between enhancers and promoters—and genetic interaction studies support the view that Mediator and Nipbl act together. Strikingly, depletion of either Nipbl or Med12 leads to characteristic changes in hox gene expression that reflect the locations of genes within their chromosomal clusters, as well as to disruption of large-scale chromosome organization around the hoxda cluster, consistent with impairment of long-range enhancer-promoter interaction. Together, these findings provide insights into both the etiology of limb defects in CdLS, and the mechanisms by which Nipbl and Mediator influence gene expression.

Vyšlo v časopise: Nipbl and Mediator Cooperatively Regulate Gene Expression to Control Limb Development. PLoS Genet 10(9): e32767. doi:10.1371/journal.pgen.1004671
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004671

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