GSE210117
Rescue of Down syndrome related deficits by Brwd1 copy number restoration in Ts65Dn mice
With an astounding incidence of ~1 in 800 births, Down syndrome (DS) is the most common chromosomal condition linked to intellectual disability worldwide. While the genetic basis of DS has been identified as a triplication of chromosome 21 (HSA21), the genes encoded from HSA21 that directly contribute to cognitive deficits remain incompletely understood. Here, we found that the HSA21-encoded chromatin effector, BRWD1, was upregulated in Down syndrome neurons and brain of trisomic mice. We showed that selective copy number restoration of Brwd1 in trisomic animals rescued deficits in hippocampal LTP, cognition and gene expression. We demonstrated that Brwd1 tightly binds the BAF chromatin remodeling complex, and that increased Brwd1 expression promotes BAF genomic mistargeting. Importantly, Brwd1 renormalization rescued aberrant BAF localization, along with associated changes in chromatin accessibility and gene expression. These findings establish BRWD1 as a key epigenomic mediator of normal neurodevelopment and an important contributor to DS-related phenotypes. Overall design: In order to confirm relevance of Ts65Dn to human DS etiology, we first performed bulk RNA-seq profiling on E17.5 Ts65Dn vs. euploid forebrain tissues. Furthermore, in order to further evaluate the effects of Brwd1 rescue within the context of adult brain, we performed bulk RNA-seq on hippocampal tissues from 6-week-old male and female animals, comparing Ts65Dn vs. euploid and Ts65Dn;Brwd1+/– genotypes .