{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:45:16Z","timestamp":1785415516442,"version":"3.56.0"},"posted":{"date-parts":[[2025,9,11]]},"group-title":"Bioinformatics","reference-count":55,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T00:00:00Z","timestamp":1757548800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["P50-HG007735"],"award-info":[{"award-number":["P50-HG007735"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["UM1-HG009442"],"award-info":[{"award-number":["UM1-HG009442"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["UM1-HG009436"],"award-info":[{"award-number":["UM1-HG009436"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["1R01AI165671"],"award-info":[{"award-number":["1R01AI165671"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"award":["W911NF-19-2-0185"],"award-info":[{"award-number":["W911NF-19-2-0185"]}],"id":[{"id":"https:\/\/ror.org\/02caytj08","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,2,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Environmental and pathogen exposure can lead to profound remodeling of the gene-regulatory landscape across human immune cell populations. Here, we present a single-nucleus chromatin accessibility atlas of human immune cells comprising 271,299 cells and 319,420 candidate regulatory elements from individuals exposed to HIV-1, COVID-19, Influenza virus, organophosphates, as well as healthy controls. Our longitudinal HIV cohort reveals epigenetic signatures of T cell exhaustion manifested in changes in the accessibility at binding sites for the FOXP family transcription factors. Upon severe exposure to SARS-Cov2 we identified changes in chromatin accessibility manifesting in a regulatory switch in cytokine networks characterized by the downregulation of the NF-\u03baB motif family, alongside concordant changes in AP-1 and IRF factor networks in CD14+ classical monocytes. By integrating single-cell profiles of DNA methylation from matched samples, we created a multimodal epigenome atlas of human immune cell states using the accessibility-derived candidate regulatory elements. Both modalities exhibit complementary epigenetic signatures at transcription factor binding sites associated with cell state, as exemplified in the process of memory formation in T-cells, where BATF, AP-1, and ETS motifs exhibit significant epigenetic covariance across both epigenomic layers. Finally, by linking potentially regulatory DNA methylation signatures to changes in chromatin accessibility in monocytes, we observe that severe COVID-19 involves selective, multiomics remodeling of epigenetic profiles at TF binding sites manifested in concordant DNA methylation and accessibility dynamics at inflammation-associated regulatory TFs.<\/jats:p>","DOI":"10.1101\/2025.09.09.675101","type":"posted-content","created":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T13:55:17Z","timestamp":1757598917000},"source":"Crossref","is-referenced-by-count":1,"title":["Dissecting epigenome dynamics in human immune cells upon viral and chemical exposure by multimodal single-cell profiling"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2641-0916","authenticated-orcid":false,"given":"Irem B.","family":"G\u00fcnd\u00fcz","sequence":"first","affiliation":[{"name":"Integrative Cellular Biology and Bioinformatics, Saarland University, 66123 Saarbr\u00fccken, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bei","family":"Wei","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek C.","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Genetics, Stanford University, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenliang","family":"Wang","sequence":"additional","affiliation":[{"name":"Genomic Analysis Laboratory, The Salk Institute for Biological Studies, 10010 N Torrey Pines Rd, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manoj","family":"Hariharan","sequence":"additional","affiliation":[{"name":"Genomic Analysis Laboratory, The Salk Institute for Biological Studies, 10010 N Torrey Pines Rd, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Todd","family":"Norell","sequence":"additional","affiliation":[{"name":"Healthspan, Resilience, and Performance, Florida Institute for Human and Machine Cognition, 40 S Alcaniz St, Pensacola, FL 32502, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy J","family":"Broderick","sequence":"additional","affiliation":[{"name":"Healthspan, Resilience, and Performance, Florida Institute for Human and Machine Cognition, 40 S Alcaniz St, Pensacola, FL 32502, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Micah T.","family":"McClain","sequence":"additional","affiliation":[{"name":"Center for Infectious Disease Diagnostics and Innovation, Division of Infectious Diseases, Duke University Medical Center, Durham, NC 27710, US"},{"name":"Durham Veterans Affairs Medical Center, Durham, NC 27705 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa L.","family":"Satterwhite","sequence":"additional","affiliation":[{"name":"Department of Civil and Environmental Engineering, Pratt School of Engineering, Duke University, Durham, NC 27708, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas W.","family":"Burke","sequence":"additional","affiliation":[{"name":"Center for Infectious Disease Diagnostics and Innovation, Division of Infectious Diseases, Duke University Medical Center, Durham, NC 27710, US"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A.","family":"Petzold","sequence":"additional","affiliation":[{"name":"Center for Infectious Disease Diagnostics and Innovation, Division of Infectious Diseases, Duke University Medical Center, Durham, NC 27710, US"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiling","family":"Shen","sequence":"additional","affiliation":[{"name":"Terasaki Institute for Biomedical Innovation, Los Angeles, CA 90024, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher W.","family":"Woods","sequence":"additional","affiliation":[{"name":"Center for Infectious Disease Diagnostics and Innovation, Division of Infectious Diseases, Duke University Medical Center, Durham, NC 27710, US"},{"name":"Durham Veterans Affairs Medical Center, Durham, NC 27705 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Vance G.","family":"Fowler","sequence":"additional","affiliation":[{"name":"Center for Infectious Disease Diagnostics and Innovation, Division of Infectious Diseases, Duke University Medical Center, Durham, NC 27710, US"},{"name":"Duke Clinical Research Institute, Durham, NC 27701 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felicia","family":"Ruffin","sequence":"additional","affiliation":[{"name":"Center for Infectious Disease Diagnostics and Innovation, Division of Infectious Diseases, Duke University Medical Center, Durham, NC 27710, US"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parinya","family":"Panuwet","sequence":"additional","affiliation":[{"name":"Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana B.","family":"Barr","sequence":"additional","affiliation":[{"name":"Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron J","family":"Wilk","sequence":"additional","affiliation":[{"name":"Stanford Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA"},{"name":"Stanford Immunology Program, Stanford University School ofMedicine, Stanford, CA"},{"name":"Department of Medicine, Stanford University School of Medicine, Stanford, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madeline J","family":"Lee","sequence":"additional","affiliation":[{"name":"Stanford Immunology Program, Stanford University School ofMedicine, Stanford, CA"},{"name":"Department of Medicine, Stanford University School of Medicine, Stanford, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Blish","sequence":"additional","affiliation":[{"name":"Stanford Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA"},{"name":"Department of Medicine, Stanford University School of Medicine, Stanford, CA"},{"name":"Chan Zuckerberg Biohub, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flora","family":"Castellino","sequence":"additional","affiliation":[{"name":"U.S. Department of Health and Human Services, Administration for Strategic Preparedness and Response, Biomedical Advanced Research and Development Authority, Washington, DC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Maria","family":"Walley","sequence":"additional","affiliation":[{"name":"Vaccitech plc, Unit 6-10, Zeus Building, Rutherford Avenue, Harwell OX11 0DF, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Evans","sequence":"additional","affiliation":[{"name":"Vaccitech plc, Unit 6-10, Zeus Building, Rutherford Avenue, Harwell OX11 0DF, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph R.","family":"Ecker","sequence":"additional","affiliation":[{"name":"Genomic Analysis Laboratory, The Salk Institute for Biological Studies, 10010 N Torrey Pines Rd, La Jolla, CA 92037, USA"},{"name":"Howard Hughes Medical Institute, The Salk Institute for Biological Studies, 10010 N Torrey Pines Rd, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5809-2321","authenticated-orcid":false,"given":"Fabian","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Integrative Cellular Biology and Bioinformatics, Saarland University, 66123 Saarbr\u00fccken, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William J.","family":"Greenleaf","sequence":"additional","affiliation":[{"name":"Department of Genetics, Stanford University, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026022708402271000_2025.09.09.675101v2.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-0799-2"},{"key":"2026022708402271000_2025.09.09.675101v2.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.08.044"},{"key":"2026022708402271000_2025.09.09.675101v2.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-0944-y"},{"key":"2026022708402271000_2025.09.09.675101v2.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2020.07.009"},{"key":"2026022708402271000_2025.09.09.675101v2.5","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20210582"},{"key":"2026022708402271000_2025.09.09.675101v2.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109793"},{"key":"2026022708402271000_2025.09.09.675101v2.7","doi-asserted-by":"publisher","DOI":"10.4103\/0972-5229.144017"},{"key":"2026022708402271000_2025.09.09.675101v2.8","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-016-1829-1"},{"key":"2026022708402271000_2025.09.09.675101v2.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.scitotenv.2018.07.143"},{"key":"2026022708402271000_2025.09.09.675101v2.10","doi-asserted-by":"publisher","DOI":"10.1002\/0471142727.mb2129s109"},{"key":"2026022708402271000_2025.09.09.675101v2.11","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-019-0332-7"},{"key":"2026022708402271000_2025.09.09.675101v2.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.07.039"},{"key":"2026022708402271000_2025.09.09.675101v2.13","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-022-05225-6"},{"key":"2026022708402271000_2025.09.09.675101v2.14","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-022-01371-3"},{"key":"2026022708402271000_2025.09.09.675101v2.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.05.039"},{"key":"2026022708402271000_2025.09.09.675101v2.16","doi-asserted-by":"publisher","DOI":"10.1101\/2023.06.29.546792"},{"key":"2026022708402271000_2025.09.09.675101v2.17","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-06355-2"},{"key":"2026022708402271000_2025.09.09.675101v2.18","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-019-0619-0"},{"key":"2026022708402271000_2025.09.09.675101v2.19","doi-asserted-by":"publisher","DOI":"10.1126\/science.abl5197"},{"key":"2026022708402271000_2025.09.09.675101v2.20","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2528-x"},{"key":"2026022708402271000_2025.09.09.675101v2.21","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4401"},{"key":"2026022708402271000_2025.09.09.675101v2.22","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-019-0206-z"},{"key":"2026022708402271000_2025.09.09.675101v2.23","doi-asserted-by":"publisher","DOI":"10.1038\/srep16833"},{"key":"2026022708402271000_2025.09.09.675101v2.24","doi-asserted-by":"publisher","DOI":"10.1097\/qad.0b013e32834bab86"},{"key":"2026022708402271000_2025.09.09.675101v2.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2023.100935"},{"key":"2026022708402271000_2025.09.09.675101v2.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.08.044"},{"key":"2026022708402271000_2025.09.09.675101v2.27","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00616-14"},{"key":"2026022708402271000_2025.09.09.675101v2.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.08.001"},{"key":"2026022708402271000_2025.09.09.675101v2.29","doi-asserted-by":"publisher","DOI":"10.1042\/ebc20190033"},{"key":"2026022708402271000_2025.09.09.675101v2.30","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaj2239"},{"key":"2026022708402271000_2025.09.09.675101v2.31","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz1001"},{"key":"2026022708402271000_2025.09.09.675101v2.32","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-019-0505-9"},{"key":"2026022708402271000_2025.09.09.675101v2.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.10.022"},{"key":"2026022708402271000_2025.09.09.675101v2.34","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-020-0633-5"},{"key":"2026022708402271000_2025.09.09.675101v2.35","doi-asserted-by":"publisher","DOI":"10.1002\/med.21361"},{"key":"2026022708402271000_2025.09.09.675101v2.36","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-022-01137-4"},{"key":"2026022708402271000_2025.09.09.675101v2.37","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1001829"},{"key":"2026022708402271000_2025.09.09.675101v2.38","doi-asserted-by":"publisher","DOI":"10.3390\/immuno2020017"},{"key":"2026022708402271000_2025.09.09.675101v2.39","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-023-04747-9"},{"key":"2026022708402271000_2025.09.09.675101v2.40","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00790-6"},{"key":"2026022708402271000_2025.09.09.675101v2.41","doi-asserted-by":"publisher","DOI":"10.1126\/science.abl5197"},{"key":"2026022708402271000_2025.09.09.675101v2.42","doi-asserted-by":"crossref","unstructured":"Wickham, H. (2016). ggplot2: Elegant Graphics for Data Analysis. Springer-Verlag New York.","DOI":"10.1007\/978-3-319-24277-4_9"},{"key":"2026022708402271000_2025.09.09.675101v2.43","unstructured":"Kassambara, A. (2023). ggpubr: \u2018ggplot2\u2019 Based Publication Ready Plots. R package version 0.6.0. https:\/\/rpkgs.datanovia.com\/ggpubr"},{"key":"2026022708402271000_2025.09.09.675101v2.44","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp328"},{"key":"2026022708402271000_2025.09.09.675101v2.45","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2528-x"},{"key":"2026022708402271000_2025.09.09.675101v2.46","unstructured":"Mueller, F . (2023). ChrAccR: Analyzing Chromatin Accessibility Data in R. R package version 0.9.21."},{"key":"2026022708402271000_2025.09.09.675101v2.47","unstructured":"Melville, J. (2023). uwot: The Uniform Manifold Approximation and Projection (UMAP) Method for Dimensionality Reduction. R package version 0.1.16. https:\/\/CRAN.R-project.org\/package=uwot"},{"key":"2026022708402271000_2025.09.09.675101v2.48","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-023-01767-y"},{"key":"2026022708402271000_2025.09.09.675101v2.49","unstructured":"Baglama, J. , Hunt, B. , & Roy, A. (2024). irlba: Fast Truncated Singular Value Decomposition and Principal Components Analysis for Large Dense and Sparse Matrices. R package version 2.3.5. https:\/\/CRAN.R-project.org\/package=irlba"},{"key":"2026022708402271000_2025.09.09.675101v2.50","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-019-1664-9"},{"key":"2026022708402271000_2025.09.09.675101v2.51","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007"},{"key":"2026022708402271000_2025.09.09.675101v2.52","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-015-0621-5"},{"key":"2026022708402271000_2025.09.09.675101v2.53","doi-asserted-by":"publisher","DOI":"10.1016\/j.xinn.2021.100141"},{"key":"2026022708402271000_2025.09.09.675101v2.54","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.05.042"},{"key":"2026022708402271000_2025.09.09.675101v2.55","doi-asserted-by":"publisher","DOI":"10.1038\/nature05563"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.09.09.675101","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T16:40:32Z","timestamp":1772210432000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.09.09.675101"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,11]]},"references-count":55,"URL":"https:\/\/doi.org\/10.1101\/2025.09.09.675101","relation":{},"subject":[],"published":{"date-parts":[[2025,9,11]]},"subtype":"preprint"}}