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

Autor: Bendl J; Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Hauberg ME; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Biomedicine, Aarhus University, Aarhus, Denmark.; The Lundbeck Foundation Initiative of Integrative Psychiatric Research (iPSYCH), Aarhus University, Aarhus, Denmark.; Centre for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark., Girdhar K; Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Im E; Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA.; Department of Psychiatry, New York University Langone Health, New York, NY, USA., Vicari JM; Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Graduate School of Biomedical Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Rahman S; Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Fernando MB; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Graduate School of Biomedical Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Townsley KG; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Graduate School of Biomedical Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Dong P; Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Misir R; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Kleopoulos SP; Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Reach SM; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Apontes P; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Zeng B; Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Zhang W; Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Voloudakis G; Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Brennand KJ; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Psychiatry, Yale University, New Haven, CT, USA., Nixon RA; Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA.; Department of Psychiatry, New York University Langone Health, New York, NY, USA.; Department of Cell Biology, New York University Langone Health, New York, NY, USA.; New York University Neuroscience Institute, New York, NY, USA., Haroutunian V; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Mental Illness Research Education and Clinical Center (MIRECC), James J. Peters VA Medical Center, Bronx, NY, USA., Hoffman GE; Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Fullard JF; Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Roussos P; Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA. panagiotis.roussos@mssm.edu.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. panagiotis.roussos@mssm.edu.; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. panagiotis.roussos@mssm.edu.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA. panagiotis.roussos@mssm.edu.; Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA. panagiotis.roussos@mssm.edu.; Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA. panagiotis.roussos@mssm.edu.; Mental Illness Research Education and Clinical Center (MIRECC), James J. Peters VA Medical Center, Bronx, NY, USA. panagiotis.roussos@mssm.edu.
Jazyk: angličtina
Zdroj: Nature neuroscience [Nat Neurosci] 2022 Oct; Vol. 25 (10), pp. 1366-1378. Date of Electronic Publication: 2022 Sep 28.
DOI: 10.1038/s41593-022-01166-7
Abstrakt: 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.
(© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
Databáze: MEDLINE
Externí odkaz: