The Three-dimensional Landscape of Cortical Chromatin Accessibility in Alzheimer's Disease

Overview

Journal Nat Neurosci

Date 2022 Sep 28

PMID 36171428

Authors

Jaroslav Bendl

Mads E Hauberg

Kiran Girdhar

Eunju Im

James M Vicari

Samir Rahman

Michael B Fernando

Kayla G Townsley

Pengfei Dong

Ruth Misir

Steven P Kleopoulos

Sarah M Reach

Pasha Apontes

Biao Zeng

Wen Zhang

Georgios Voloudakis

Kristen J Brennand

Ralph A Nixon

Vahram Haroutunian

Gabriel E Hoffman

John F Fullard

Panos Roussos

Affiliations

Soon will be listed here.

Abstract

To characterize the dysregulation of chromatin accessibility in Alzheimer'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.

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References

Andrews S, Fulton-Howard B, Goate A . Interpretation of risk loci from genome-wide association studies of Alzheimer's disease. Lancet Neurol. 2020; 19(4):326-335. PMC: 8176461. DOI: 10.1016/S1474-4422(19)30435-1. View

Marzi S, Leung S, Ribarska T, Hannon E, Smith A, Pishva E . A histone acetylome-wide association study of Alzheimer's disease identifies disease-associated H3K27ac differences in the entorhinal cortex. Nat Neurosci. 2018; 21(11):1618-1627. DOI: 10.1038/s41593-018-0253-7. View

Klein H, McCabe C, Gjoneska E, Sullivan S, Kaskow B, Tang A . Epigenome-wide study uncovers large-scale changes in histone acetylation driven by tau pathology in aging and Alzheimer's human brains. Nat Neurosci. 2018; 22(1):37-46. PMC: 6516529. DOI: 10.1038/s41593-018-0291-1. View

Li P, Marshall L, Oh G, Jakubowski J, Groot D, He Y . Epigenetic dysregulation of enhancers in neurons is associated with Alzheimer's disease pathology and cognitive symptoms. Nat Commun. 2019; 10(1):2246. PMC: 6529540. DOI: 10.1038/s41467-019-10101-7. View

Raj T, Li Y, Wong G, Humphrey J, Wang M, Ramdhani S . Integrative transcriptome analyses of the aging brain implicate altered splicing in Alzheimer's disease susceptibility. Nat Genet. 2018; 50(11):1584-1592. PMC: 6354244. DOI: 10.1038/s41588-018-0238-1. View

Nott A, Holtman I, Coufal N, Schlachetzki J, Yu M, Hu R . Brain cell type-specific enhancer-promoter interactome maps and diseaserisk association. Science. 2019; 366(6469):1134-1139. PMC: 7028213. DOI: 10.1126/science.aay0793. View

Kozlenkov A, Wang M, Roussos P, Rudchenko S, Barbu M, Bibikova M . Substantial DNA methylation differences between two major neuronal subtypes in human brain. Nucleic Acids Res. 2015; 44(6):2593-612. PMC: 4824074. DOI: 10.1093/nar/gkv1304. View

Wang M, Beckmann N, Roussos P, Wang E, Zhou X, Wang Q . The Mount Sinai cohort of large-scale genomic, transcriptomic and proteomic data in Alzheimer's disease. Sci Data. 2018; 5:180185. PMC: 6132187. DOI: 10.1038/sdata.2018.185. View

Fillenbaum G, van Belle G, Morris J, Mohs R, Mirra S, Davis P . Consortium to Establish a Registry for Alzheimer's Disease (CERAD): the first twenty years. Alzheimers Dement. 2008; 4(2):96-109. PMC: 2808763. DOI: 10.1016/j.jalz.2007.08.005. View

10.

Braak H, Braak E . Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991; 82(4):239-59. DOI: 10.1007/BF00308809. View

11.

Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K . Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol. 2006; 112(4):389-404. PMC: 3906709. DOI: 10.1007/s00401-006-0127-z. View

12.

Morris J . The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 1993; 43(11):2412-4. DOI: 10.1212/wnl.43.11.2412-a. View

13.

Nelson P, Alafuzoff I, Bigio E, Bouras C, Braak H, Cairns N . Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol. 2012; 71(5):362-81. PMC: 3560290. DOI: 10.1097/NEN.0b013e31825018f7. View

14.

Fullard J, Hauberg M, Bendl J, Egervari G, Cirnaru M, Reach S . An atlas of chromatin accessibility in the adult human brain. Genome Res. 2018; 28(8):1243-1252. PMC: 6071637. DOI: 10.1101/gr.232488.117. View

15.

Hauberg M, Creus-Muncunill J, Bendl J, Kozlenkov A, Zeng B, Corwin C . Common schizophrenia risk variants are enriched in open chromatin regions of human glutamatergic neurons. Nat Commun. 2020; 11(1):5581. PMC: 7643171. DOI: 10.1038/s41467-020-19319-2. View

16.

Hu B, Won H, Mah W, Park R, Kassim B, Spiess K . Neuronal and glial 3D chromatin architecture informs the cellular etiology of brain disorders. Nat Commun. 2021; 12(1):3968. PMC: 8233376. DOI: 10.1038/s41467-021-24243-0. View

17.

Hoffman G, Schadt E . variancePartition: interpreting drivers of variation in complex gene expression studies. BMC Bioinformatics. 2016; 17(1):483. PMC: 5123296. DOI: 10.1186/s12859-016-1323-z. View

18.

Fulco C, Nasser J, Jones T, Munson G, Bergman D, Subramanian V . Activity-by-contact model of enhancer-promoter regulation from thousands of CRISPR perturbations. Nat Genet. 2019; 51(12):1664-1669. PMC: 6886585. DOI: 10.1038/s41588-019-0538-0. View

19.

Mifsud B, Tavares-Cadete F, Young A, Sugar R, Schoenfelder S, Ferreira L . Mapping long-range promoter contacts in human cells with high-resolution capture Hi-C. Nat Genet. 2015; 47(6):598-606. DOI: 10.1038/ng.3286. View

20.

Corces M, Shcherbina A, Kundu S, Gloudemans M, Fresard L, Granja J . Single-cell epigenomic analyses implicate candidate causal variants at inherited risk loci for Alzheimer's and Parkinson's diseases. Nat Genet. 2020; 52(11):1158-1168. PMC: 7606627. DOI: 10.1038/s41588-020-00721-x. View