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The interferon response induces innate effector and adaptive cellular responses crucial for viral clearance and the establishment of long-lasting immune memory. Although these antiviral processes are primarily characterized at the transcriptional level, the epigenetic mechanisms that orchestrate the cellular transcriptional output during infection remain understudied. Technological advances in systems immunology and virology have revealed dynamic changes in the cellular epigenetic landscape following infection, and their contextual roles in the fine-tuning of antiviral defense. This minireview covers our current understanding of how DNA methylation, post-translational modifications of histones, and chromatin remodelers are dynamically reprogrammed during respiratory virus infections, and the distinct strategies that respiratory viruses employ to subvert epigenetic control. We place further emphasis on cell-type-specific programs and the biological factors that alter the epigenetic landscape and regulate the balance between protective or pathogenic immune responses to infection.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.01783-25","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T12:39:28Z","timestamp":1779280768000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Unraveling the layers of epigenetic control in respiratory antiviral defense"],"prefix":"10.1128","volume":"100","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-4955-7111","authenticated-orcid":true,"given":"Matthew I.","family":"McFadden","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00c01js51","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbial Infection and Immunity, Infectious Diseases Institute, College of 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