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Open Access Highly Accessed Research article

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

Yanhai Guo1*, Wei Kang2, Xiaoying Lei1, Yongnian Li3, An Xiang1, Yonglan Liu1, Jinrong Zhao1, Ju Zhang1 and Zhen Yan1

Author Affiliations

1 State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, School of Pharmacy, Fourth Military Medical University, 169 West Changle Road, Xi’an, 710032, China

2 Department of Clinical Laboratory, Affiliated Hospital of Xi’an Medical University, Xi’an, 710077, China

3 Department of Infectious Diseases, 323 Hospital, Xi’an, 710000, China

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BMC Genomics 2012, 13:563  doi:10.1186/1471-2164-13-563

Published: 22 October 2012

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).

Conclusion

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.

Keywords:
Hepatitis B virus; Hepatitis B core protein; Chromatin immunoprecipitation microarray; ChIP-on-chip; Gene expression; DNA-protein interaction