Interferon drives HCV scarring of the epigenome and creates targetable vulnerabilities following viral clearance

Abstract

Background and Aims Chronic HCV infection is a leading etiologic driver of cirrhosis and ultimately 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. Approach and Results 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 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 (IFN‐α) or a direct‐acting antiviral (DAA). Our data demonstrate that HCV infection profoundly affects the epigenome (particularly enhancers); HCV shares epigenetic targets with interferon‐α targets; and 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 IFN‐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 elucidate 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.

Molecular pathogenesis and systemic therapies for hepatocellular carcinoma

“…Specific molecular and immune classes have been defined, which integrate the current molecular knowledge of this cancer 6 . In this regard, immune 11 and epigenetic mechanisms 7 , 24 – 26 might have major consequences in understanding the onset, evolution and treatment of this malignancy. Overall, the main molecular alterations and pathogenic processes involved in HCC development have been extensively reviewed elsewhere 1 , 4 , 8 …”

SHP2 inhibition enhances Yes-associated protein–mediated liver regeneration in murine partial hepatectomy models

“…Thus, we explored whether SHP2 inhibition altered YAP signaling, specifically in a noncancerous paradigm. We first assessed YAP signaling in Hu1545, a TERT-immortalized human hepatocyte cell line ( 29 ). In this cell line, we observed increased YAP tyrosine phosphorylation (pYAP Y357 ), a known activating posttranslational modification, in NSC-treated cells ( Figure 2A ).…”

Mechanism and Therapeutic Opportunities of Histone Modifications in Chronic Liver Disease

“…Inhibition of histone H4 methylation was found in genes essential for hepatocarcinogenesis with changed expression in HCV proteins-induced cell lines, which might be responsible for the hepatocarcinogenesis in chronic hepatitis C ( Table 1 ) ( Duong et al, 2010 ). In addition, a decrease of H3K27me3, a silencing mark of transcription, was found in HCV-infected cells ( Hlady et al, 2021 ). These studies indicate that alterations in histone methylation status in hepatocytes after viruses infection regulate the expression of genes which may exacerbate disease progression.…”