@article{507d24249c724decbe08cce415eef00b,
title = "The three-dimensional landscape of cortical chromatin accessibility in Alzheimer{\textquoteright}s disease",
abstract = "To characterize the dysregulation of chromatin accessibility in Alzheimer{\textquoteright}s disease (AD), we generated 636 ATAC-seq libraries from neuronal and nonneuronal nuclei isolated from the superior temporal gyrus and entorhinal cortex of 153 AD cases and 56 controls. By analyzing a total of ~20 billion read pairs, we expanded the repertoire of known open chromatin regions (OCRs) in the human brain and identified cell-type-specific enhancer–promoter interactions. We show that interindividual variability in OCRs can be leveraged to identify cis-regulatory domains (CRDs) that capture the three-dimensional structure of the genome (3D genome). We identified AD-associated effects on chromatin accessibility, the 3D genome and transcription factor (TF) regulatory networks. For one of the most AD-perturbed TFs, USF2, we validated its regulatory effect on lysosomal genes. Overall, we applied a systematic approach to understanding the role of the 3D genome in AD. We provide all data as an online resource for widespread community-based analysis.",
author = "Jaroslav Bendl and Hauberg, {Mads E.} and Kiran Girdhar and Eunju Im and Vicari, {James M.} and Samir Rahman and Fernando, {Michael B.} and Townsley, {Kayla G.} and Pengfei Dong and Ruth Misir and Kleopoulos, {Steven P.} and Reach, {Sarah M.} and Pasha Apontes and Biao Zeng and Wen Zhang and Georgios Voloudakis and Brennand, {Kristen J.} and Nixon, {Ralph A.} and Vahram Haroutunian and Hoffman, {Gabriel E.} and Fullard, {John F.} and Panos Roussos",
note = "Funding Information: We thank the patients and families who donated material for these studies. We thank the members of the Roussos laboratory for thoughtful advice and critique and the computational resources and staff expertise provided by the Scientific Computing at the Icahn School of Medicine at Mount Sinai. This study was supported by grants from the National Institute on Aging, NIH grants R01-AG067025 (P.R. and V.H.), R01-AG065582 (P.R. and V.H.) and R01-AG050986 (P.R.) and by grants from the National Institute of Mental Health, NIH grants, R56-MH101454 (K.J.B.), R01-MH106056 (P.R. and K.J.B.), R01-MH109897 (P.R. and K.J.B.) and R01-MH121074 (K.J.B.). J.B. was supported in part by Alzheimer{\textquoteright}s Association Research Fellowship AARF-21-722200. K.G. was supported in part by Alzheimer{\textquoteright}s Association Research Fellowship AARF-21-722582. G.E.H. and P.D. were supported in part by NARSAD Young Investigator grants 26313 and 29683, respectively, from the Brain & Behavior Research Foundation. S.P.K. is a recipient of an NIH LRP award. Research reported in this paper was supported by the Office of Research Infrastructure of the National Institutes of Health under award numbers S10OD018522 and S10OD026880. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: We thank the patients and families who donated material for these studies. We thank the members of the Roussos laboratory for thoughtful advice and critique and the computational resources and staff expertise provided by the Scientific Computing at the Icahn School of Medicine at Mount Sinai. This study was supported by grants from the National Institute on Aging, NIH grants R01-AG067025 (P.R. and V.H.), R01-AG065582 (P.R. and V.H.) and R01-AG050986 (P.R.) and by grants from the National Institute of Mental Health, NIH grants, R56-MH101454 (K.J.B.), R01-MH106056 (P.R. and K.J.B.), R01-MH109897 (P.R. and K.J.B.) and R01-MH121074 (K.J.B.). J.B. was supported in part by Alzheimer{\textquoteright}s Association Research Fellowship AARF-21-722200. K.G. was supported in part by Alzheimer{\textquoteright}s Association Research Fellowship AARF-21-722582. G.E.H. and P.D. were supported in part by NARSAD Young Investigator grants 26313 and 29683, respectively, from the Brain & Behavior Research Foundation. S.P.K. is a recipient of an NIH LRP award. Research reported in this paper was supported by the Office of Research Infrastructure of the National Institutes of Health under award numbers S10OD018522 and S10OD026880. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright} 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",
year = "2022",
month = oct,
doi = "10.1038/s41593-022-01166-7",
language = "English",
volume = "25",
pages = "1366--1378",
journal = "Nature Neuroscience",
issn = "1097-6256",
publisher = "Nature Publishing Group",
number = "10",
}