Telbivudine treatment corrects HBV-induced epigenetic alterations in liver cells of patients with chronic hepatitis B.
Hepatitis B virus (HBV) alters the expression of host cellular genes to support its replication and survival and to promote the liver cell injury. However, the underlying mechanism remained incompletely understood. In this study, we investigated HBV-induced epigenetic changes in HepG2 cells by profiling the landscapes of the active histone modification mark H3K4me3 and repressive mark H3K27me3 using chromatin immunoprecipitation-sequencing. HBV caused the altered histone modifications at thousands of genomic loci, which are critically involved in HBV entry, inflammation, fibrosis and carcinogenesis of host cells. Interestingly, treatment of the HBV-transformed HepG2 cells with the anti-HBV drug Telbivudine substantially restored the H3K4me3 level to that of untransformed HepG2 cells. More importantly, our analysis of liver samples from control and chronic hepatitis B patients revealed that treatment of the patients with Telbivudine not only corrected the target gene expression but also the epigenetic modification of critical genes. In addition, the expression of the histone methyltransferases SMYD3 and EZH2 that regulate histone H3-specific methylation showed no difference in HepG2 cell with or without HBV existence. Thus, our data suggest that abnormal histone modifications might critically involved in HBV-mediated liver pathogenesis and Telbivudine therapy might benefit patients with HBV-related chronic infection, liver cirrhosis and even hepatic carcinoma.


CONCLUSIONS
Telbivudine substantially restores in vitro and in vivo HBV-caused abnormal expressions and histone H3K4me3 and H3K27me3 modifications at thousands of genomic loci that are involved in the pathogenesis of liver cells, revealing a novel mechanism for HBV-mediated liver damage.
Institute of Immunology, PLA, Third Military Medical University, Chongqing 400038, PR China.
Yi
Y
Tian
Dongjing
D
Ni
Weibing
W
Yang
Yi
Y
Zhang
Keji
K
Zhao
Jianxun
J
Song
Qing
Q
Mao
Zhiqiang
Z
Tian
Jennifer C
JC
van Velkinburgh
Di
D
Yang
Yuzhang
Y
Wu
Bing
B
Ni
D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016022:Case-Control Studies; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005786:Gene Expression Regulation; D056945:Hep G2 Cells / Q000187:drug effects; D006515:Hepatitis B virus / Q000472:pathogenicity; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000235:genetics* / Q000821:virology; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006657:Histones / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000821:virology*; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology / Q000821:virology; D008745:Methylation; D063151:Polycomb Repressive Complex 2 / Q000235:genetics; D000077712:Telbivudine; D013936:Thymidine / Q000031:analogs & derivatives* / Q000627:therapeutic use
D000998:Antiviral Agents; D002843:Chromatin; D006657:Histones; D000077712:Telbivudine; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2; C506278:SMYD3 protein, human; D013936:Thymidine