Decreasing Wapl dosage partially corrects transcriptome phenotypes in Nipbl-/+ embryonic mouse brain

Cohesin rings interact with DNA and modulate expression of thousands of genes. NIPBL loads cohesin onto chromosomes and WAPL takes it off. Heterozygous mutations in NIPBL lead to a developmental disorder called Cornelia de Lange Syndrome. Nipbl heterozygous mice are a good model for this disease but mutations in WAPL were not known to cause disease or gene expression changes in mammals. Here we show dysregulation of more than 1000 genes in Wapl heterozygous embryonic mouse brains. The patterns of dysregulation are highly similar to those seen in Nipbl heterozygotes, suggesting that Wapl mutations may also cause disease in humans. Since WAPL and NIPL have opposite effects on cohesin's association with DNA, we asked whether a heterozygous Wapl mutation could correct phenotypes seen in Nipbl heterozygous mice. In fact, both gene expression and embryonic growth are partially corrected. Our data are consistent with the view that cohesin dynamics play a key role in regulating gene expression. ### Competing Interest Statement The authors have declared no competing interest.