The three-dimensional landscape of cortical chromatin accessibility in Alzheimer’s disease

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. HoffmanJohn F. Fullard, Panos Roussos

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1366-1378
Number of pages13
JournalNature Neuroscience
Volume25
Issue number10
DOIs
StatePublished - Oct 2022

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