Epigenetic modification induced by hepatitis B virus X protein via interaction with de novo DNA methyltransferase DNMT3A

被引：159

作者：

Zheng, Da-Li ^{[1
,2
]}

Zhang, Li ^{[2
]}

Cheng, Na ^{[1
,2
]}

Xu, Xiao ^{[1
,2
]}

Deng, Qing ^{[1
,2
]}

Teng, Xiao-Mei ^{[1
,2
]}

Wang, Ke-Sheng ^{[2
]}

Zhang, Xin ^{[2
]}

Huang, Jian ^{[2
]}

Han, Ze-Guang ^{[1
,2
]}

机构：

[1] Shanghai Jiao Tong Univ, Sch Med, Rui Jin Hosp, Natl Human Genome Ctr, Shanghai 200025, Peoples R China

[2] Chinese Natl Human Genome Ctr Shanghai, Shanghai MOST Key Lab Dis & Hlth Genom, Shanghai 201203, Peoples R China

来源：

JOURNAL OF HEPATOLOGY | 2009年 / 50卷 / 02期

关键词：

Hepatitis B virus X protein; Epigenetic modification; DNMT3A; Hepatocellular carcinoma; HUMAN HEPATOCELLULAR-CARCINOMA; GENE-EXPRESSION; TRANSGENIC MICE; HBX PROTEIN; HYPOMETHYLATION; METHYLATION; HEPATOCARCINOGENESIS; REPLICATION; ACTIVATION; RECEPTOR;

D O I：

10.1016/j.jhep.2008.10.019

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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 historic 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-1 receptor and metallothionein-1F and subsequently silenced their transcription via tie 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. (C) 2008 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

引用

页码：377 / 387

页数：11

共 46 条

[1] High expression of insulin-like growth factor binding protein-3 is correlated with lower portal invasion and better prognosis in human hepatocellular carcinoma [J].