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

Nature Neuroscience volume 25, pages 1366–1378 (2022)Cite this article

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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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Fig. 1: Large-scale chromatin accessibility analysis in the human brain.
Fig. 2: Variance component analysis of gene expression.
Fig. 3: Linking distal regulatory OCRs (OCRABC) to genes using the ABC method.
Fig. 4: Disease-associated chromatin changes.
Fig. 5: Gene set enrichment analysis using general gene sets.
Fig. 6: Mapping of TFs to cell types and AD-related phenotypes.
Fig. 7: Definition of neuronal and nonneuronal CRDs.
Fig. 8: Disease-associated perturbations in CRDs.

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Data availability

Raw data (FASTQ files) and processed data (BigWig files, peaks, and raw/normalized count matrices) are available via the AD Knowledge Portal (https://adknowledgeportal.org). The AD Knowledge Portal is a platform for accessing data, analyses and tools generated by the Accelerating Medicines Partnership (AMP-AD) Target Discovery Program and other National Institute on Aging (NIA)-supported programs to enable open-science practices and accelerate translational learning. The data, analyses and tools are shared early in the research cycle without a publication embargo on secondary use. Data are available for general research use according to the following requirements for data access and data attribution (https://adknowledgeportal.org/DataAccess/Instructions). For access to the content described in this manuscript, see https://doi.org/10.7303/syn21513145. Browsable UCSC genome browser tracks of processed data are available at http://icahn.mssm.edu/atacad.

External validation sets: MSBB RNA-seq of postmortem brains (Synapse ID: syn3157743), ATAC-seq on FANS-sorted NeuN+/− from postmortem brains (Synapse ID: syn20755767), H3K9ac ChIP–seq of postmortem brains (Synapse ID: syn4896408). ATAC-seq iPSC-derived neurons overexpressing MAPT gene (GEO: GSE97409), ROSMAP RNA-seq of postmortem brains (Synapse ID: syn3388564), fine-mapped eQTLs (https://alkesgroup.broadinstitute.org/LDSCORE/LDSC_QTL/, version ‘FE_META_TISSUE_GTEx_Brain_MaxCPP’), CTCF ChIP–seq peaks on human neural cell (GEO: GSE127577). OCRs (peaks) from The Cancer Genome Atlas (https://gdc.cancer.gov/about-data/publications/ATACseq-AWG), BOCA/BOCA2 brain epigenome atlas (https://icahn.mssm.edu/boca, https://icahn.mssm.edu/boca2), Dong. et al. 2021 (Synapse ID: syn25716684), Nott et al. 2019 (dbGaP ID: phs001373), and Meuleman et al. 2020 (ENCODE ID: ENCSR857UZV), fine-mapped eQTLs (https://alkesgroup.broadinstitute.org/LDSCORE/LDSC_QTL/, version ‘FE_META_TISSUE_GTEx_Brain_MaxCPP’), CTCF ChIP–seq on human neural cell (GEO: GSE127577), The Cancer Genome Atlas (https://gdc.cancer.gov/about-data/publications/ATACseq-AWG), REMC (http://www.roadmapepigenomics.org), mSigDB 7.0 (http://www.gsea-msigdb.org/), dbSNP v.151 (https://www.ncbi.nlm.nih.gov/snp/), PsychENCODE SNP-array: Capstone collection (https://psychencode.synapse.org/).

Code availability

The code used to perform the analysis described in this study is available at https://doi.org/10.7303/syn34034120.

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Acknowledgements

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’s Association Research Fellowship AARF-21-722200. K.G. was supported in part by Alzheimer’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.

Author information

Author notes

  1. Kristen J. Brennand

    Present address: Department of Psychiatry, Yale University, New Haven, CT, USA

  2. These authors contributed equally: Jaroslav Bendl, Mads E. Hauberg, Kiran Girdhar.

  3. These authors jointly supervised this work: John F. Fullard, Panos Roussos.

Authors and Affiliations

  1. Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Jaroslav Bendl, Kiran Girdhar, James M. Vicari, Samir Rahman, Pengfei Dong, Steven P. Kleopoulos, Biao Zeng, Wen Zhang, Georgios Voloudakis, Gabriel E. Hoffman, John F. Fullard & Panos Roussos

  2. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Jaroslav Bendl, Mads E. Hauberg, Kiran Girdhar, 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, Vahram Haroutunian, John F. Fullard & Panos Roussos

  3. Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Jaroslav Bendl, Kiran Girdhar, James M. Vicari, Samir Rahman, Pengfei Dong, Steven P. Kleopoulos, Biao Zeng, Wen Zhang, Gabriel E. Hoffman, John F. Fullard & Panos Roussos

  4. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Jaroslav Bendl, Mads E. Hauberg, Kiran Girdhar, James M. Vicari, Samir Rahman, Pengfei Dong, Ruth Misir, Steven P. Kleopoulos, Sarah M. Reach, Pasha Apontes, Biao Zeng, Wen Zhang, Georgios Voloudakis, Kristen J. Brennand, Vahram Haroutunian, John F. Fullard & Panos Roussos

  5. Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Jaroslav Bendl, Kiran Girdhar, James M. Vicari, Samir Rahman, Pengfei Dong, Ruth Misir, Steven P. Kleopoulos, Sarah M. Reach, Pasha Apontes, Biao Zeng, Wen Zhang, Gabriel E. Hoffman, John F. Fullard & Panos Roussos

  6. Department of Biomedicine, Aarhus University, Aarhus, Denmark

    Mads E. Hauberg

  7. The Lundbeck Foundation Initiative of Integrative Psychiatric Research (iPSYCH), Aarhus University, Aarhus, Denmark

    Mads E. Hauberg

  8. Centre for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark

    Mads E. Hauberg

  9. Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA

    Eunju Im, Ralph A. Nixon & Panos Roussos

  10. Department of Psychiatry, New York University Langone Health, New York, NY, USA

    Eunju Im & Ralph A. Nixon

  11. Graduate School of Biomedical Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    James M. Vicari, Michael B. Fernando & Kayla G. Townsley

  12. Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Michael B. Fernando, Kayla G. Townsley, Kristen J. Brennand & Vahram Haroutunian

  13. Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Michael B. Fernando & Kristen J. Brennand

  14. Department of Cell Biology, New York University Langone Health, New York, NY, USA

    Ralph A. Nixon

  15. New York University Neuroscience Institute, New York, NY, USA

    Ralph A. Nixon

  16. Mental Illness Research Education and Clinical Center (MIRECC), James J. Peters VA Medical Center, Bronx, NY, USA

    Vahram Haroutunian & Panos Roussos

Authors
  1. Jaroslav Bendl
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  2. Mads E. Hauberg
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  3. Kiran Girdhar
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  4. Eunju Im
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  5. James M. Vicari
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  6. Samir Rahman
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  7. Michael B. Fernando
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  8. Kayla G. Townsley
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  9. Pengfei Dong
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  10. Ruth Misir
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  11. Steven P. Kleopoulos
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  12. Sarah M. Reach
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  13. Pasha Apontes
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  14. Biao Zeng
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  15. Wen Zhang
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  16. Georgios Voloudakis
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  17. Kristen J. Brennand
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  18. Ralph A. Nixon
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  19. Vahram Haroutunian
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  20. Gabriel E. Hoffman
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  21. John F. Fullard
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  22. Panos Roussos
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Contributions

R.A.N., V.H. and P.R. conceived of and designed the project. V.H. provided human brain tissue. J.F.F. and P.R. designed experimental strategies for epigenome profiling in human postmortem tissue. R.M., S.K., S.M.R. and J.F.F. performed ATAC-seq data generation. S.R. performed Hi-C data generation. P.A. performed ChIP–seq data generation. E.I., J.V. and R.A.N. performed USF2 in vitro validation studies. M.B.F., K.G.T., J.V., S.R. and K.J.B. performed the CRISPRi in vitro validation studies. J.B., M.E.H., K.G., G.E.H. and P.R. designed analytical strategies. J.B., M.E.H., K.G. and G.E.H. conducted initial bioinformatics sample processing and quality control. J.B., M.E.H., K.G. and G.E.H. developed and performed all downstream omics data analyses and interpreted results. B.Z. performed eQTL fine-mapping analysis. W.Z. and G.V. performed transcriptome imputation analysis. P.D. performed ChIP–seq and Hi-C data analysis. J.B., M.E.H., K.G., G.E.H., J.F.F. and P.R. wrote the manuscript with the help of all authors. G.E.H., J.F.F. and P.R. supervised overall data generation and analysis.

Corresponding author

Correspondence to Panos Roussos.

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Nature Neuroscience thanks the anonymous reviewers for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Methods. Supplementary Figures 1–35 and Supplementary Note.

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Supplementary Tables 1–19.

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Bendl, J., Hauberg, M.E., Girdhar, K. et al. The three-dimensional landscape of cortical chromatin accessibility in Alzheimer’s disease. Nat Neurosci 25, 1366–1378 (2022). https://doi.org/10.1038/s41593-022-01166-7

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  • DOI: https://doi.org/10.1038/s41593-022-01166-7

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