Genomic responses to hepatitis B virus (HBV) infection in primary human hepatocytes.

// Pierre-Benoit Ancey 1 , Barbara Testoni 2 , Marion Gruffaz 2 , Marie-Pierre Cros 1 , Geoffroy Durand 3 , Florence Le Calvez-Kelm 3 , David Durantel 2 , Zdenko Herceg 1 , Hector Hernandez-Vargas 1 1 Epigenetics Group, International Agency for Research on Cancer (IARC), Lyon, France 2 INSERM U1052, Molecular Physiopathology and New Treatments of Viral Hepatitis, Centre de Recherche en Cancerologie (CRCL), Lyon, France 3 Genetic Cancer Susceptibility Group, International Agency for Research on Cancer (IARC), Lyon, France Correspondence to: Hector Hernandez-Vargas, e-mail: vargash@iarc.fr Keywords: HBV, hepatitis, methylome, HM450, transcriptome Received: August 17, 2015      Accepted: October 14, 2015      Published: November 02, 2015 ABSTRACT Viral infections are able to modify the host’s cellular programs, with DNA methylation being a biological intermediate in this process. The extent to which viral infections deregulate gene expression and DNA methylation is not fully understood. In the case of Hepatitis B virus (HBV), there is evidence for an interaction between viral proteins and the host DNA methylation machinery. We studied the ability of HBV to modify the host transcriptome and methylome, using naturally infected primary human hepatocytes to better mimic the clinical setting. Gene expression was especially sensitive to culture conditions, independently of HBV infection. However, we identified non-random changes in gene expression and DNA methylation occurring specifically upon HBV infection. There was little correlation between expression and methylation changes, with transcriptome being a more sensitive marker of time-dependent changes induced by HBV. In contrast, a set of differentially methylated sites appeared early and were stable across the time course experiment. Finally, HBV-induced DNA methylation changes were defined by a specific chromatin context characterized by CpG-poor regions outside of gene promoters. These data support the ability of HBV to modulate host cell expression and methylation programs. In addition, it may serve as a reference for studies addressing the genome-wide consequences of HBV infection in human hepatocytes.