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 Roussos, John C. Schimenti, Allyson K. Friedman, Li Shen, Robert D. Blitzer, Alfred J. Robison, Gerald R. Crabtree and Ian Maze ()
Additional contact information
Sasha L. Fulton: Icahn School of Medicine at Mount Sinai
Wendy Wenderski: Stanford Medical School
Ashley E. Lepack: Icahn School of Medicine at Mount Sinai
Andrew L. Eagle: Michigan State University
Tomas Fanutza: Icahn School of Medicine at Mount Sinai
Ryan M. Bastle: Icahn School of Medicine at Mount Sinai
Aarthi Ramakrishnan: Icahn School of Medicine at Mount Sinai
Emma C. Hays: Icahn School of Medicine at Mount Sinai
Arianna Neal: Icahn School of Medicine at Mount Sinai
Jaroslav Bendl: Icahn School of Medicine at Mount Sinai
Lorna A. Farrelly: Icahn School of Medicine at Mount Sinai
Amni Al-Kachak: Icahn School of Medicine at Mount Sinai
Yang Lyu: Icahn School of Medicine at Mount Sinai
Bulent Cetin: Icahn School of Medicine at Mount Sinai
Jennifer C. Chan: Icahn School of Medicine at Mount Sinai
Tina N. Tran: Cornell University
Rachael L. Neve: Massachusetts Institute of Technology
Randall J. Roper: Indiana University-Purdue University
Kristen J. Brennand: Icahn School of Medicine at Mount Sinai
Panos Roussos: Icahn School of Medicine at Mount Sinai
John C. Schimenti: Cornell University
Allyson K. Friedman: City University of New York-Hunter College
Li Shen: Icahn School of Medicine at Mount Sinai
Robert D. Blitzer: Icahn School of Medicine at Mount Sinai
Alfred J. Robison: Michigan State University
Gerald R. Crabtree: Stanford Medical School
Ian Maze: Icahn School of Medicine at Mount Sinai

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract 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.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-022-34200-0 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34200-0

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-34200-0

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().