Unknown,Transcriptomics,Genomics,Proteomics

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Genome-wide analysis of histone methylation reveals chromatin state-based regulation of host cellular gene expression induced by hepatitis B viruses (DGE dataset)

ABSTRACT: Hepatitis B virus (HBV) is a hepatotropic virus that can regulate many host cellular gene expressions participating in the HBV life cycle, liver inflammation and hepatocellular injury. However, the underlying mechanism of differential gene expression is not understood. We report here a genome-wide analysis of histone methylation on two histone H3 lysine residues (H3K4me3 and H3K27me3) and gene expression profiles in HepG2 and HepG2.2.15 cells. We found that specific correlation exists between gene expression and the amounts of H3K4me3 (positive correlation) and H3K27me3 (negative correlation) across the gene body. These correlations displayed three distinct modes (repressive, active and poised), reflecting different functions of these genes in the HBV life cycle, liver inflammation and hepatocellular injury. Furthermore, a permissive chromatin state of each gene was established by a combination of different histone modifications. Our findings reveal a complex regulation by histone methylation in differential gene expression and suggest that histone methylation may be responsible for the HBV life cycle, liver inflammation and hepatocellular injury induced by HBV. A large-scale analysis of gene expression of 2 different cell types (HepG2, HepG2.2.15) using a digital gene expression (DGE) tag profiling approach.

ORGANISM(S): Homo sapiens

SUBMITTER: Ni Bing

PROVIDER: E-GEOD-35464 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Hepatitis B virus (HBV) causes both acute and chronic liver inflammation. Approximately 600,000 CHB patients each year die of HBV-related diseases such as cirrhosis and liver cancer. Therefore, CHB remains a global health concern. Although there have been anti-HBV agents for treating CHB, they have some limitations including viral-drug resistance and adverse effects. Type III IFN or IFN-λ is promising to use as anti-HBV agents because of its anti-viral activities like type I IFNs. In addition, the expression of its receptor, IFNLR1, is limited only in epithelial cells including hepatocytes. Thus, treatment with IFN-lambda results in less side effects compared to IFN-alpha treatment. IFN-lambdas have been shown to inhibit the replication of several viruses including IAV, DENV, EMCV, HIV, HCV, and HBV; however, there have been no studies on the effects of IFN-λ3, the highest activity among other subtypes, on HBV replication. Therefore, this study aims to determine antiviral activities of IFN-λ3 against HBV replication and to investigate its molecular mechanism responsible for suppressing HBV propagation. The results showed that HBV transcripts and amount of intracellular HBV DNA were decreased in HepG2.2.15 cells, stable HBV-transfected hepatoblastoma cell line, treated with IFN-λ3 in a dose-dependent manner. This indicated that IFN-λ3 could inhibit HBV replication. Next, we performed quantitative proteomics to investigate the proteome changes in HepG2.2.15 treated with IFN-λ3. The proteins that changed their expressions were involved in several biological processes such as defense to viral infection, immune responses, cell-cell adhesion, transcription, translation, and metabolism. We further confirmed the proteomics results by immunoblotting assay. Consistent with MS data, it found that the expression of OAS3, SAMHD1 and STAT1 were increased as a result of IFN-λ3 stimulation. These results indicated that proteomics results were reproducible and reliable. Finally, we proposed 3 possible mechanisms involved in suppressing HBV replication including i.) IFN-λ3 induced anti-viral proteins affecting many steps in HBV life cycle ii.) IFN-λ3 promoted antigen processing and antigen presentation and iii.) IFN-λ3 rescued RIG-I signaling to promote both type I and type III IFN production.

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Genome-wide analysis of histone methylation reveals chromatin state-based regulation of host cellular gene expression induced by hepatitis B viruses (DGE dataset)

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