BACKGROUND/AIMS: The hepatitis B virus X protein (HBx) has been implicated as a potential trigger of the epigenetic deregulation of some genes, but the underlying mechanisms remain unknown. The aim of this study was to identify underlying mechanisms involved in HBx-mediated epigenetic modification. METHODS: Interactions between HBx and DNA methyltransferase (DNMT) or histone deacetylase-1 (HDAC1) were assessed by co-immunoprecipitation. DNA methylation of gene promoters was detected by bisulfite sequencing, and HBx-mediated protein binding to gene regulatory elements was evaluated by chromatin immunoprecipitation. Target gene transcriptional activity was measured by real-time polymerase chain reaction. RESULTS: HBx can interact directly with DNMT3A and HDAC1. HBx recruited DNMT3A to the regulatory promoters of interleukin-4 receptor and metallothionein-1F and subsequently silenced their transcription via de novo DNA methylation. By contrast, the transcription of CDH6 and IGFBP3 was triggered by HBx through the deprivation of DNMT3A from their promoters. Transcriptional levels of target genes in hepatocellular carcinoma (HCC) specimens were strongly correlated with the occurrence of HBx. CONCLUSIONS: The interaction of HBx and DNMT3A facilitates cellular epigenetic modification (via regional hypermethylation or hypomethylation) at distinct genomic loci, providing an alternative mechanism within HBx-mediated transcriptional regulation, and a profound understanding of hepatitis and HCC pathogenesis.
BACKGROUND/AIMS: The hepatitis B virus X protein (HBx) has been implicated as a potential trigger of the epigenetic deregulation of some genes, but the underlying mechanisms remain unknown. The aim of this study was to identify underlying mechanisms involved in HBx-mediated epigenetic modification. METHODS: Interactions between HBx and DNA methyltransferase (DNMT) or histone deacetylase-1 (HDAC1) were assessed by co-immunoprecipitation. DNA methylation of gene promoters was detected by bisulfite sequencing, and HBx-mediated protein binding to gene regulatory elements was evaluated by chromatin immunoprecipitation. Target gene transcriptional activity was measured by real-time polymerase chain reaction. RESULTS:HBx can interact directly with DNMT3A and HDAC1. HBx recruited DNMT3A to the regulatory promoters of interleukin-4 receptor and metallothionein-1F and subsequently silenced their transcription via de novo DNA methylation. By contrast, the transcription of CDH6 and IGFBP3 was triggered by HBx through the deprivation of DNMT3A from their promoters. Transcriptional levels of target genes in hepatocellular carcinoma (HCC) specimens were strongly correlated with the occurrence of HBx. CONCLUSIONS: The interaction of HBx and DNMT3A facilitates cellular epigenetic modification (via regional hypermethylation or hypomethylation) at distinct genomic loci, providing an alternative mechanism within HBx-mediated transcriptional regulation, and a profound understanding of hepatitis and HCC pathogenesis.
Authors: Zdenko Herceg; Marie-Pierre Lambert; Karin van Veldhoven; Christiana Demetriou; Paolo Vineis; Martyn T Smith; Kurt Straif; Christopher P Wild Journal: Carcinogenesis Date: 2013-06-07 Impact factor: 4.944
Authors: Xu You Liu; Shao Hui Tang; Sheng Lan Wu; Yu Hong Luo; Ming Rong Cao; Hong Ke Zhou; Xiang Wu Jiang; Jian Chang Shu; Cai Qun Bie; Si Min Huang; Zhan Hong Zheng; Fei Gao Journal: Am J Cancer Res Date: 2015-02-15 Impact factor: 6.166
Authors: Sarah Leonard; Wenbin Wei; Jennifer Anderton; Martina Vockerodt; Martin Rowe; Paul G Murray; Ciaran B Woodman Journal: J Virol Date: 2011-07-13 Impact factor: 5.103
Authors: Betty L Slagle; Ourania M Andrisani; Michael J Bouchard; Caroline G L Lee; J-H James Ou; Aleem Siddiqui Journal: Hepatology Date: 2015-03-09 Impact factor: 17.425