{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T23:50:53Z","timestamp":1791071453663,"version":"4.1.0"},"reference-count":32,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2021,12,15]],"date-time":"2021-12-15T00:00:00Z","timestamp":1639526400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2021,12,15]],"date-time":"2021-12-15T00:00:00Z","timestamp":1639526400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>Chronic HCV infection is a leading etiologic driver of cirrhosis and ultimately HCC. Of the approximately 71 million individuals chronically infected with HCV, 10%\u201020% are expected to develop severe liver complications in their lifetime. Epigenetic mechanisms including DNA methylation and histone modifications become profoundly disrupted in disease processes including liver disease.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>To understand how HCV infection influences the epigenome and whether these events remain as \u201cscars\u201d following cure of chronic HCV infection, we mapped genome\u2010wide DNA methylation, four key regulatory histone modifications (H3K4me3, H3K4me1, H3K27ac, and H3K27me3), and open chromatin in parental and HCV\u2010infected immortalized hepatocytes and the Huh7.5 HCC cell line, along with DNA methylation and gene\u2010expression analyses following elimination of HCV in these models through treatment with interferon\u2010\u03b1 (IFN\u2010\u03b1) or a direct\u2010acting antiviral (DAA). Our data demonstrate that HCV infection profoundly affects the epigenome (particularly enhancers); HCV shares epigenetic targets with interferon\u2010\u03b1 targets; and an overwhelming majority of epigenetic changes induced by HCV remain as \u201cscars\u201d on the epigenome following viral cure. Similar findings are observed in primary human patient samples cured of chronic HCV infection. Supplementation of IFN\u2010\u03b1\/DAA antiviral regimens with DNA methyltransferase inhibitor 5\u2010aza\u20102\u2019\u2010deoxycytidine synergizes in reverting aberrant DNA methylation induced by HCV. Finally, both HCV\u2010infected and cured cells displayed a blunted immune response, demonstrating a functional effect of epigenetic scarring.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Integration of epigenetic and transcriptional data elucidate key gene deregulation events driven by HCV infection and how this may underpin the long\u2010term elevated risk for HCC in patients cured of HCV due to epigenome scarring.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.32111","type":"journal-article","created":{"date-parts":[[2021,8,13]],"date-time":"2021-08-13T10:06:24Z","timestamp":1628849184000},"page":"983-996","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":36,"title":["Interferon drives HCV scarring of the epigenome and creates targetable vulnerabilities following viral clearance"],"prefix":"10.1097","volume":"75","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2829-4237","authenticated-orcid":false,"given":"Ryan A.","family":"Hlady","sequence":"first","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics,Mayo Clinic,Rochester,Minnesota,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics,Mayo Clinic,Rochester,Minnesota,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis Y.","family":"El Khoury","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics,Mayo Clinic,Rochester,Minnesota,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aesis","family":"Luna","sequence":"additional","affiliation":[{"name":"Department of Pathology,Yale School of Medicine,New Haven,Connecticut,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kien","family":"Pham","sequence":"additional","affiliation":[{"name":"Department of Pathology,Yale School of Medicine,New Haven,Connecticut,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qunfeng","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine,New Jersey Medical School,Rutgers,The State University of New Jersey,Newark,New Jersey,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4007-9166","authenticated-orcid":false,"given":"Jeong\u2010Heon","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology,Mayo Clinic,Rochester,Minnesota,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaos T.","family":"Pyrsopoulos","sequence":"additional","affiliation":[{"name":"Department of Medicine,Rutgers New Jersey Medical School,Newark,New Jersey,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pathology,Yale School of Medicine,New Haven,Connecticut,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7508-3328","authenticated-orcid":false,"given":"Keith D.","family":"Robertson","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics,Mayo Clinic,Rochester,Minnesota,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2021,12,15]]},"reference":[{"key":"hep32111-bib-0001-20250824","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1002\/hep.26141","article-title":"Global epidemiology of hepatitis C virus infection: new estimates of age\u2010specific antibody to HCV 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