title: Hepatitis B viral core protein disrupts human host gene expression by binding to promoter regions.
abstract: BACKGROUND
  The 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.
  
  
  RESULTS
  Whole-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).
  
  
  CONCLUSIONS
  HBc 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.
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, School of Pharmacy, Fourth Military Medical University, 169 West Changle Road, Xi'an, 710032, China. gyanhai@fmmu.edu.cn
authors.forename: Yanhai
authors.initials: Y
authors.lastname: Guo
authors.forename: Wei
authors.initials: W
authors.lastname: Kang
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Lei
authors.forename: Yongnian
authors.initials: Y
authors.lastname: Li
authors.forename: An
authors.initials: A
authors.lastname: Xiang
authors.forename: Yonglan
authors.initials: Y
authors.lastname: Liu
authors.forename: Jinrong
authors.initials: J
authors.lastname: Zhao
authors.forename: Ju
authors.initials: J
authors.lastname: Zhang
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yan
mesh_terms: D000328:Adult; D047369:Chromatin Immunoprecipitation; D005260:Female; D015967:Gene Expression Regulation, Viral; D015894:Genome, Human; D006509:Hepatitis B / Q000235:genetics*; D006512:Hepatitis B Core Antigens / Q000378:metabolism*; D006515:Hepatitis B virus / Q000235:genetics / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D000090063:Proto-Oncogene Mas; D014758:Viral Core Proteins / Q000378:metabolism*; D055815:Young Adult
chemical_list: D006512:Hepatitis B Core Antigens; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D014758:Viral Core Proteins