Hepatitis B viral core protein disrupts human host gene expression by binding to promoter regions

Abstract

BackgroundThe core protein (HBc) of hepatitis B virus (HBV) has been implicated in the malignant transformation of chronically-infected hepatocytes and displays pleiotropic functions, including RNA- and DNA-binding activities. However, the mechanism by which HBc interacts with the human genome to exert effects on hepatocyte function remains unknown. This study investigated the distribution of HBc binding to promoters in the human genome and evaluated its effects on the related genes’ expression.ResultsWhole-genome chromatin immunoprecipitation microarray (ChIP-on-chip) analysis was used to identify HBc-bound human gene promoters. Gene Ontology and pathway analyses were performed on related genes. The quantitative polymerase chain reaction assay was used to verify ChIP-on-chip results. Five novel genes were selected for luciferase reporter assay evaluation to assess the influence of HBc promoter binding. The HBc antibody immunoprecipitated approximately 3100 human gene promoters. Among these, 1993 are associated with known biological processes, and 2208 regulate genes with defined molecular functions. In total, 1286 of the related genes mediate primary metabolic processes, and 1398 encode proteins with binding activity. Sixty-four of the promoters regulate genes related to the mitogen-activated protein kinase (MAPK) pathways, and 41 regulate Wnt/beta-catenin pathway genes. The reporter gene assay indicated that HBc binding up-regulates proto-oncogene tyrosine-protein kinase (SRC), type 1 insulin-like growth factor receptor (IGF1R), and neurotrophic tyrosine kinase receptor 2 (NTRK2), and down-regulates v-Ha-ras Harvey rat sarcoma viral oncogene (HRAS).ConclusionHBc has the ability to bind a large number of human gene promoters, and can disrupt normal host gene expression. Manipulation of the transcriptional profile in HBV-infected hepatocytes may represent a key pathogenic mechanism of HBV infection.

Capsid Assembly Modulators Have a Dual Mechanism of Action in Primary Human Hepatocytes Infected with Hepatitis B Virus

“…Capsid formation is an essential step in the generation of infectious virions and in the amplification of cccDNA in the nucleus (8)(9)(10). In addition, core was reported to be recruited onto the viral chromatin (29,30) and to modulate host promoter regions (31). Therefore, antiviral intervention by targeting the multiple functions of the core protein with small molecules provides a promising strategy to disrupt HBV infection at multiple steps in the viral life cycle.…”

“…In fact, the conversion of rcDNA to cccDNA is a complex process which requires disassembly of the capsid, deproteinization of the rcDNA, and the ligation of rcDNA to cccDNA (34). The latter was shown to involve Ku80, a protein of the host's DNA repair pathway (31). In addition, polymerase was found to be crucial for cccDNA formation (35), and the observation that a host cell polymerase is involved in the conversion from rcDNA to cccDNA is in line with our results that NA treatment did not inhibit cccDNA formation.…”

Attenuation of enoyl coenzyme A hydratase short chain 1 expression in gastric cancer cells inhibits cell proliferation and migration in vitro

“…In recent years, roles in cancer cell proliferation and apoptosis have been reported for it. ECHS1 directly interacts with hepatitis B surface antigen (HBsAg) [18,24]. Binding of HBsAg reduces ECHS1 levels and induces apoptosis of the hepatocellular carcinoma HepG2 cells [18,25].…”

Hepatitis viruses exploitation of host DNA methyltransferases functions

“…Mutations accumulate over time generating different strains with a relevant impact on the course of HBV infection [46]. Although the X protein cannot establish an infection by itself, in cultured hepatocytes, it was able to dysregulate cellular genes and pathways [47,48] and it is found to be associated with HCC, as it is able to impair the cellular proliferation [49]. The influence of HBV infection on the aberrant DNA methylation in HCCs was already demonstrated in vivo [50,51] and in vitro [52].…”