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

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...

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Published in:Nature neuroscience 2022-10, Vol.25 (10), p.1366-1378
Main Authors: Bendl, Jaroslav, Hauberg, Mads E., Girdhar, Kiran, Im, Eunju, Vicari, James M., Rahman, Samir, Fernando, Michael B., Townsley, Kayla G., Dong, Pengfei, Misir, Ruth, Kleopoulos, Steven P., Reach, Sarah M., Apontes, Pasha, Zeng, Biao, Zhang, Wen, Voloudakis, Georgios, Brennand, Kristen J., Nixon, Ralph A., Haroutunian, Vahram, Hoffman, Gabriel E., Fullard, John F., Roussos, Panos
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cited_by cdi_FETCH-LOGICAL-c474t-b60fd7013206298a3bb98592b1e6cc05922aff5377143855d90a449e512de6e03
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container_issue 10
container_start_page 1366
container_title Nature neuroscience
container_volume 25
creator Bendl, Jaroslav
Hauberg, Mads E.
Girdhar, Kiran
Im, Eunju
Vicari, James M.
Rahman, Samir
Fernando, Michael B.
Townsley, Kayla G.
Dong, Pengfei
Misir, Ruth
Kleopoulos, Steven P.
Reach, Sarah M.
Apontes, Pasha
Zeng, Biao
Zhang, Wen
Voloudakis, Georgios
Brennand, Kristen J.
Nixon, Ralph A.
Haroutunian, Vahram
Hoffman, Gabriel E.
Fullard, John F.
Roussos, Panos
description 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. The authors generated the largest epigenome atlas of postmortem brains with Alzheimer’s disease. They reported regulatory genomic signatures associated with AD, including variability in open chromatin regions, transcription factor networks and cis -regulatory domains.
doi_str_mv 10.1038/s41593-022-01166-7
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Accessibility
Alzheimer Disease - genetics
Alzheimer's disease
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title The three-dimensional landscape of cortical chromatin accessibility in Alzheimer’s disease
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