Rescue of Down syndrome related deficits by Brwd1 copy number restoration
Trisomy 21 [Down syndrome/DS] is the most common genetic cause of intellectual disability worldwide. Despite much progress in the genetic characterization of DS, the genes encoded from chromosome 21 (HSA21) that directly contribute to intellectual disability remain incompletely understood. Here, we found that a largely uncharacterized chromatin effector protein, BRWD1, is triplicated in DS neurons and brain of trisomic mice. We demonstrated that selective copy number restoration of Brwd1 in DS animals rescues transcriptional, synaptic and cognitive deficits. We showed that Brwd1 binds to the neuronal BAF chromatin remodeling complex, and that such interactions promote BAF's genomic mistargeting in DS-like brain. Brwd1 renormalization in trisomic animals rescues these aberrant chromatin events. These findings thus establish BRWD1 as a critical epigenomic mediator of DS related phenotypes. Overall design: RNA-seq performed in E16 forebrain-derived primary neuronal cultures mouse brain, and embryonic forebrain (mixed male female) and adult hippocampus (male and female), and ChIP-seq for Smarca2/4 and neuronal ATAC-seq were performed in adult male hippocampus to examine the impact of Brwd1 copy number restoration in DS-like (Ts65Dn) mice on transcriptional patterning, BAF complex recruitment and chromatin accessibility. Three genotypes were compared: euploid vs. Ts65Dn vs. Ts65Dn; Brwd1+/-.