Interferon drives HCV scarring of the epigenome and creates targetable vulnerabilities following viral clearance
| Autor: | Xia Zhao, Qunfeng Wu, Aesis Luna, Chen Liu, Ryan A. Hlady, Jeong Heon Lee, Nikolaos Pyrsopoulos, Kien Pham, Louis El Khoury, Keith D. Robertson |
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| Rok vydání: | 2021 |
| Předmět: |
Carcinoma
Hepatocellular Hepatitis C virus Hepacivirus medicine.disease_cause Antiviral Agents Article Liver disease Epigenome Histone code Medicine Humans Epigenetics Epigenomics Hepatology business.industry Liver Neoplasms virus diseases Interferon-alpha Hepatitis C Hepatitis C Chronic medicine.disease digestive system diseases Immunology DNA methylation business |
| Zdroj: | Hepatology |
| ISSN: | 1527-3350 |
| Popis: | Background & aims Chronic hepatitis C viral (HCV) infection is a leading etiologic driver of cirrhosis and ultimately hepatocellular carcinoma (HCC). Of the approximately 71 million individuals chronically infected with HCV, 10-20% 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. Methods To understand how HCV infection influences the epigenome and whether these events remain as 'scars' following cure of chronic HCV infection, we mapped genome-wide DNA methylation, four key regulatory histone modifications (H3K4me3, H3K4me1, H3K27ac, and H3K27me3) and open chromatin by ATAC-seq in parental and HCV-infected immortalized hepatocytes and the Huh7.5 HCC cell line, along with DNA methylation and gene expression analyses following elimination of HCV in these models through treatment with interferon-α or a direct-acting antiviral (DAA). Results Our data demonstrate that HCV infection profoundly impacts the epigenome (particularly enhancers), HCV shares epigenetic targets with interferon-α targets, an overwhelming majority of epigenetic changes induced by HCV remain as 'scars' on the epigenome following viral cure Similar findings are observed in primary human patient samples cured of chronic HCV infection. Supplementation of interferon-α/DAA antiviral regimens with DNA methyltransferase inhibitor 5-aza-2'deoxycytidine synergizes in reverting aberrant DNA methylation induced by HCV. Finally, both HCV-infected and cured cells displayed a blunted immune response, demonstrating a functional effect of epigenetic scarring. Conclusions Integration of epigenetic and transcriptional data elucidates key gene deregulation events driven by HCV infection and how this may underpin the long-term elevated risk for HCC in patients cured of HCV due to epigenome scarring. |
| Databáze: | OpenAIRE |
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