Rescue of deficits by Brwd1 copy number restoration in the Ts65Dn mouse model of Down syndrome

Sasha L. Fulton, Wendy Wenderski, Ashley E. Lepack, Andrew L. Eagle, Tomas Fanutza, Ryan M. Bastle, Aarthi Ramakrishnan, Emma C. Hays, Arianna Neal, Jaroslav Bendl, Lorna A. Farrelly, Amni Al-Kachak, Yang Lyu, Bulent Cetin, Jennifer C. Chan, Tina N. Tran, Rachael L. Neve, Randall J. Roper, Kristen J. Brennand, Panos RoussosJohn C. Schimenti, Allyson K. Friedman, Li Shen, Robert D. Blitzer, Alfred J. Robison, Gerald R. Crabtree, Ian Maze

Research output: Contribution to journalArticlepeer-review


With an 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 neurons derived from iPS cells from an individual with Down syndrome 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.

Original languageEnglish
Article number6384
JournalNature Communications
Issue number1
StatePublished - Dec 2022


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