Hepatitis C Virus-induced Differential Transcriptional Traits in Host Cells After Persistent Infection Elimination by Direct-Acting Antivirals In Cell Culture
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE267834 | GEO | 2024/07/11
REPOSITORIES: GEO
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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.
2021-09-23 | GSE168178 | GEO
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.
2021-09-23 | GSE168185 | GEO
Project description:Hepatitis C virus (HCV) remains a significant public health threat as new 1.75 million HCV infections emerged worldwide. The majority of these infections become persistently infected, while around 30 % spontaneously eliminate the virus. Clinical factors for viral clarification are related to HCV interaction with host immune system, but little is known about the consequences after HCV spontaneous resolution. These individuals are difficult to recruit and study as acute infection is usually asymptomatic, and they will not be identified unless it progress to chronic infection. The study of peripheral blood mononuclear cells (PBMCs) of these patients is crucial, as PBMCs are one of the main HCV extrahepatic reservoirs, and its transcriptional profile provide us information of innate and adaptive immune response against HCV infection. Our research shows novel insight on molecular consequences of spontaneous resolution after an acute HCV infection. 96 Individuals with different HCV exposure status were recruited: spontaneous resolved, chronic infected and healthy controls; and the microRNA profile of their PBMCs were analyzed. Our results indicate similar disruption of miRNA expression on HCV chronic patients and those who spontaneously clarified the infection, compared to control patients. The disrupted miRNAs formed a signature of 21 miRNAs that mainly regulate lipid metabolism. This is the first report showing miRNA profile similarities between chronic HCV patients and spontaneous resolved individuals. Thus, our results suggest that HCV infection promotes molecular alterations in PBMCs that will last longer after HCV spontaneous eradication. This evidences open up new prospects in the management of individuals who spontaneously clarified infection, as they should be monitored and followed to dismiss future HCV-related complications, such us liver diseases complications. The identified miRNA signature could be used as biomarker to monitor HCV fingerprint on HCV-exposed patients.
2019-06-21 | E-MTAB-8023 | biostudies-arrayexpress
Project description:Chronic liver disease and cancer are global health challenges. The role of the circadian clock (CC) as a regulator of physiology and disease is well established in animal models. However, in human liver the identity of circadian genes and their epigenetic regulation is unknown. Here, we unraveled the circadian transcriptome and epigenome of human hepatocytes using a human liver chimeric mouse model. We identified genes coding for transcription factors, chromatin modifiers, and critical enzymes which are expressed rhythmically in human hepatocytes, and which differ from the mouse liver circadian transcriptome. Moreover, we show that hepatitis C virus (HCV) infection, a major cause of liver disease and cancer world-wide, perturbs the human hepatocellular clock leading to an activation of pathways mediating steatosis, fibrosis and cancer. The HCV-disrupted rhythmic hepatic pathways remained deregulated in patients cured of HCV suggesting a major role in liver cancer development, and in the identification of therapeutic targets.
2024-08-02 | GSE200809 | GEO
Project description:Chronic liver disease and cancer are global health challenges. The role of the circadian clock (CC) as a regulator of physiology and disease is well established in animal models. However, in human liver the identity of circadian genes and their epigenetic regulation is unknown. Here, we unraveled the circadian transcriptome and epigenome of human hepatocytes using a human liver chimeric mouse model. We identified genes coding for transcription factors, chromatin modifiers, and critical enzymes which are expressed rhythmically in human hepatocytes, and which differ from the mouse liver circadian transcriptome. Moreover, we show that hepatitis C virus (HCV) infection, a major cause of liver disease and cancer world-wide, perturbs the human hepatocellular clock leading to an activation of pathways mediating steatosis, fibrosis and cancer. The HCV-disrupted rhythmic hepatic pathways remained deregulated in patients cured of HCV suggesting a major role in liver cancer development, and in the identification of therapeutic targets.
2024-08-02 | GSE200811 | GEO
Project description:Chronic liver disease and cancer are global health challenges. The role of the circadian clock (CC) as a regulator of physiology and disease is well established in animal models. However, in human liver the identity of circadian genes and their epigenetic regulation is unknown. Here, we unraveled the circadian transcriptome and epigenome of human hepatocytes using a human liver chimeric mouse model. We identified genes coding for transcription factors, chromatin modifiers, and critical enzymes which are expressed rhythmically in human hepatocytes, and which differ from the mouse liver circadian transcriptome. Moreover, we show that hepatitis C virus (HCV) infection, a major cause of liver disease and cancer world-wide, perturbs the human hepatocellular clock leading to an activation of pathways mediating steatosis, fibrosis and cancer. The HCV-disrupted rhythmic hepatic pathways remained deregulated in patients cured of HCV suggesting a major role in liver cancer development, and in the identification of therapeutic targets.
2024-08-02 | GSE200810 | GEO
Project description:Although treatment of chronic hepatitis C virus (HCV) infection with direct acting antivirals (DAAs) results in high rates of cure, liver fibrosis does not resolve immediately after HCV eradication. Resolution of fibrosis occurs in some, but not all patients, after HCV cure, and hepatic decompensation and hepatocellular carcinoma can still occur in patients with pre-existing cirrhosis. We hypothesized that evaluation of the host liver proteome in the context of HCV treatment would provide insight into how inflammatory and fibrinogenic pathways change upon HCV eradication. We evaluated the whole liver proteome and phosphoproteome using paired liver biopsies from 8 HCV-infected patients collected before or immediately after treatment with DAAs in clinical trials. We identify interferon stimulated proteins as the predominant pathways that decrease with HCV treatment, which is consistent with previous analyses of the liver transcriptome during DAA therapy. While there was no change in the proteome of pathways associated with liver fibrosis, we identified a decrease in the phosphoproteome signature for ERK1/ERK2 as a result of HCV treatment. Conclusion: There is a reduction in the endogenous interferon-mediated antiviral response and alterations in the phosphoproteome that may precede resolution of fibrosis in the liver immediately after treatment of HCV with DAAs.
2023-03-11 | PXD024846 | Pride
Project description:Hepatitis C virus (HCV)-induced chronic liver disease is one of the leading causes of hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying HCC development following chronic HCV infection remain poorly understood. MicroRNAs (miRNAs) play an important role in cellular homeostasis within the liver and deregulation of the miRNome has been associated with liver disease including HCC. While host miRNAs are essential for HCV replication, viral infection in turn appears to induce alterations of intrahepatic miRNA networks. Although the cross-talk between HCV and liver cell miRNAs most likely contributes to liver disease pathogenesis, the functional involvement of miRNAs in HCV-driven hepatocyte injury and HCC remains elusive. Here, we combined a hepatocyte-like based model system, high-throughput small RNA-sequencing, computational analysis and functional studies to investigate HCV-miRNA interactions that may contribute to liver disease and HCC. Profiling analyses indicated that HCV infection differentially regulated the expression of 72 miRNAs by at least two-fold including miRNAs that were previously described to target genes associated with inflammation, fibrosis and cancer development. Further investigation demonstrated that miR-146a-5p was consistently increased in HCV-infected hepatocyte-like cells and primary human hepatocytes as well as in liver tissues from HCV-infected patients. Genome-wide microarray and computational analyses indicated that miR-146a-5p over-expression is related to liver disease and HCC development. Furthermore, we showed that miR-146a-5p positively impacts on late steps of the viral replication cycle thereby increasing HCV infection. Collectively, our data indicate that the HCV-induced increase in miR-146a-5p expression both promotes viral infection and is relevant for pathogenesis of liver disease.
2016-05-09 | GSE74014 | GEO
Project description:End stage liver disease due to Hepatitis C Virus (HCV) infection is a major health concern worldwide. Liver fibrosis following chronic HCV infection plays a pivotal role in loss of liver function and end stage liver disease. However the dynamics and molecular events that lead to fibrosis in HCV infection are poorly defined. Therefore, we determined the influence of HCV infection in altering the miRNA expression levels which can modulate immune responses to HCV leading to fibrosis. Analysis of the miRNA expression profiles of HCV infected liver biopsies revealed that 45 miRNAs were differentially expressed in the HCV infected liver when compared to normal livers. In silico target prediction of these differentially expressed miRNAs indicated that their targets include chemokine/cytokine signaling, cell cycle genes and extracellular matrix protein gene expression. Gene expression profiling using whole genome microarray demonstrated that 1320 genes were differentially expressed in chronic HCV liver when compared to normal. These genes could be functionally grouped into those involved in cell cycle regulation, cytokines and chemokines expression, cell adhesion, intracellular signaling and enzymes. Further pathway analysis using GeneGo software identified cell adhesion, cytoskeleton remodeling, cytokine signaling and metabolic pathways as the major pathways activated in chronic HCV. Combinatorial target prediction analysis of miRNA expression along with gene expression analysis indicated that differentially expressed microRNAs in HCV significantly impact transforming growth factor beta (TGF-?) signaling pathway, cell adhesion (integrin expression), chemokine signaling, Notch signaling and cell-cycle( Cyclin D,K) regulation. Overall these results demonstrate that chronic HCV infection induces specific miRNA signatures that will modulate genes involved in the cytoskeletal remodeling and cytokine signaling that can promote the development of fibrosis following HCV infection. Liver biopsies from chronic HCV patients and control liver biopsies from normal subjects (donor liver prior to transplantation) were used to analyze the miRNA and gene expression profile. Patients with HBV and/or HIV were excluded from the study. This Series represents the mRNA gene expression profiling data only.
2012-06-14 | E-GEOD-38226 | biostudies-arrayexpress
Project description:Hepatitis C virus (HCV)-induced chronic liver disease is one of the leading causes of hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying HCC development following chronic HCV infection remain poorly understood. MicroRNAs (miRNAs) play an important role in cellular homeostasis within the liver and deregulation of the miRNome has been associated with liver disease including HCC. While host miRNAs are essential for HCV replication, viral infection in turn appears to induce alterations of intrahepatic miRNA networks. Although the cross-talk between HCV and liver cell miRNAs most likely contributes to liver disease pathogenesis, the functional involvement of miRNAs in HCV-driven hepatocyte injury and HCC remains elusive. Here, we combined a hepatocyte-like based model system, high-throughput small RNA-sequencing, computational analysis and functional studies to investigate HCV-miRNA interactions that may contribute to liver disease and HCC. Profiling analyses indicated that HCV infection differentially regulated the expression of 72 miRNAs by at least two-fold including miRNAs that were previously described to target genes associated with inflammation, fibrosis and cancer development. Further investigation demonstrated that miR-146a-5p was consistently increased in HCV-infected hepatocyte-like cells and primary human hepatocytes as well as in liver tissues from HCV-infected patients. Genome-wide microarray and computational analyses indicated that miR-146a-5p over-expression is related to liver disease and HCC development. Furthermore, we showed that miR-146a-5p positively impacts on late steps of the viral replication cycle thereby increasing HCV infection. Collectively, our data indicate that the HCV-induced increase in miR-146a-5p expression both promotes viral infection and is relevant for pathogenesis of liver disease. To explore the functional relevance of miR-146a-5p up-regulation, we performed a genome-wide transcriptomic analysis of hepatocyte-like cells upon ectopic miR-146a-5p expression.
2016-05-09 | GSE79340 | GEO