@article{446f0a2be9ab46d288dfc5c66c58ea35,
title = "Rescue of deficits by Brwd1 copy number restoration in the Ts65Dn mouse model of Down syndrome",
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.",
author = "Fulton, {Sasha L.} and Wendy Wenderski and Lepack, {Ashley E.} and Eagle, {Andrew L.} and Tomas Fanutza and Bastle, {Ryan M.} and Aarthi Ramakrishnan and Hays, {Emma C.} and Arianna Neal and Jaroslav Bendl and Farrelly, {Lorna A.} and Amni Al-Kachak and Yang Lyu and Bulent Cetin and Chan, {Jennifer C.} and Tran, {Tina N.} and Neve, {Rachael L.} and Roper, {Randall J.} and Brennand, {Kristen J.} and Panos Roussos and Schimenti, {John C.} and Friedman, {Allyson K.} and Li Shen and Blitzer, {Robert D.} and Robison, {Alfred J.} and Crabtree, {Gerald R.} and Ian Maze",
note = "Funding Information: We would like to thank Dr. William Mobley (UC San Diego School of Medicine) for expert advice on our work, Dr. Anita Bhattacharyya (University of Wisconsin) for providing us with DS hiPSCs, and Dr. Alexey Soshnev (The Rockefeller University) for help with illustrations. We would also like to acknowledge the Cornell University Stem Cell and Transgenic Core Facility for their help with CRISPR microinjections to generate Brwd1FLAG-HAmice (special thanks to Robert Munroe and Christian Abratte). This work was supported by grants from the National Institutes of Health: R01 HD097088 (I.M.), F99 NS125774 (S.L.F.), F31 MH116588 and F99 NS118735 (W.W.), R15 HD090603 (R.J.R.), R01 HD082568 (J.C.S.), SC2 GM122646 (A.K.F.), R01 MH111604 (A.J.R.), R01 NS085171 (A.J.R.), R01 DA040621 (A.J.R.), R01 CA163915 (G.R.C.), and R37 NS046789 (G.R.C.), as well as awards from: March of Dimes (I.M.), Alfred P. Sloan Foundation Fellowship in Neuroscience (I.M.), Avielle Foundation (A.J.R.), CIRM RB4-05886 (G.R.C.), SFARI (G.R.C.) and the Howard Hughes Medical Institute (I.M. and G.R.C.). Funding Information: We would like to thank Dr. William Mobley (UC San Diego School of Medicine) for expert advice on our work, Dr. Anita Bhattacharyya (University of Wisconsin) for providing us with DS hiPSCs, and Dr. Alexey Soshnev (The Rockefeller University) for help with illustrations. We would also like to acknowledge the Cornell University Stem Cell and Transgenic Core Facility for their help with CRISPR microinjections to generate Brwd1 mice (special thanks to Robert Munroe and Christian Abratte). This work was supported by grants from the National Institutes of Health: R01 HD097088 (I.M.), F99 NS125774 (S.L.F.), F31 MH116588 and F99 NS118735 (W.W.), R15 HD090603 (R.J.R.), R01 HD082568 (J.C.S.), SC2 GM122646 (A.K.F.), R01 MH111604 (A.J.R.), R01 NS085171 (A.J.R.), R01 DA040621 (A.J.R.), R01 CA163915 (G.R.C.), and R37 NS046789 (G.R.C.), as well as awards from: March of Dimes (I.M.), Alfred P. Sloan Foundation Fellowship in Neuroscience (I.M.), Avielle Foundation (A.J.R.), CIRM RB4-05886 (G.R.C.), SFARI (G.R.C.) and the Howard Hughes Medical Institute (I.M. and G.R.C.). FLAG-HA Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = dec,
doi = "10.1038/s41467-022-34200-0",
language = "English",
volume = "13",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}