Project description: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 cured infection, and 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 changes 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.

Project description: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 cured infection, and 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 changes 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. Lay summary: Despite cure of hepatitis C viral (HCV) infection, patients remain at increased long-term risk for liver cancer. This study aimed to discover whether this effect was mediated through the epigenome. Using a novel cell culture system, we find that normal epigenetic marks and gene expression are disrupted by chronic HCV infection, and that these disrupted patterns are not restored following HCV cure. Moreover, the epigenetic disruptions caused by HCV are very similar to the natural interferon response that is typically key to clearing viral infections. Epigenetically disrupted pathways therefore contribute to suppression of innate immunity and increased risk for liver cancer in patients cured of HCV, but also reveal potential vulnerabilities that could be targeted pharmacologically.

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Single-cell transcriptomic analyses of T cells in chronic HCV-infected patients dominated by DAA-induced interferon signaling changes

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