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IFN-α inhibits HBV transcription and replication by promoting HDAC3-mediated de-2-hydroxyisobutyrylation of histone H4K8 on HBV cccDNA minichromosome in liver
文献摘要：
The epigenetic modification of hepatitis B virus(HBV)covalently closed circular DNA(cccDNA)plays a crucial role in cccDNA transcription and viral persistence.Interferon-α(IFN-α)is a pivotal agent against HBV cccDNA.However,the mechanism by which IFN-α modulates the epigenetic regulation of cccDNA remains poorly understood.In this study,we report that IFN-α2b enhances the histone deacetylase 3(HDAC3)-mediated de-2-hydroxyisobutyrylation of histone H4 lysine 8(H4K8)on HBV cccDNA minichromosome to restrict the cccDNA transcription in liver.By screening acetyltransferases and deacetylases,we identified that HDAC3 was an effective restrictor of HBV transcription and replication.Moreover,we found that HDAC3 was able to mediate the de-2-hydroxyisobutyrylation of H4K8 in HBV-expressing hepatoma cells.Then,the 2-hydroxyisobutyrylation of histone H4K8(H4K8hib)was identified on the HBV cccDNA minichromosome,promoting the HBV transcription and replication.The H4K8hib was regulated by HDAC3 depending on its deacetylase domain in the system.The low level of HDAC3 and high level of H4K8hib were observed in the liver tissues from HBV-infected human liver-chimeric mice.The levels of H4K8hib on HBV cccDNA minichromosome were significantly elevated in the liver biopsy specimens from clinical hepatitis B patients,which was consistent with the high transcriptional activity of cccDNA.Strikingly,IFN-α2b effectively facilitated the histone H4K8 de-2-hydroxyisobutyrylation mediated by HDAC3 on the HBV cccDNA minichromosome in primary human hepatocytes and hepatoma cells,leading to the inhibition of HBV transcription and replication.Our finding provides new insights into the mechanism by which IFN-α modulates the epigenetic regulation of HBV cccDNA minichromosome.
文献关键词：
中图分类号：
[1] 医药、卫生（R） / 药学（R9） / 药理学（R96） / 实验药理学（R965）
[2] 医药、卫生（R） / 基础医学（R3） / 病理学（R36） / 病理过程（R364）
[3] 医药、卫生（R） / 神经病学与精神病学（R74） / 神经病学（R741）
作者姓名：
Li-na Zhao;Hong-feng Yuan;Yu-fei Wang;Hao-lin Yun;Wei Zheng;Ying Yuan;Yu Geng;Man Zhao;Lian-yun Feng;Xiao-dong Zhang
作者机构：
Department of Cancer Research,Institute of Molecular Biology,College of Life Sciences,Nankai University,Tianjin 300071,China;Department of Gastrointestinal Cancer Biology,Tianjin Cancer Institute,Liver Cancer Center,Tianjin Medical University Cancer Institute and Hospital,National Clinical Research Center for Cancer,Tianjin 300060,China
文献出处：
中国药理学报（英文版）
引用格式：
[1]Li-na Zhao;Hong-feng Yuan;Yu-fei Wang;Hao-lin Yun;Wei Zheng;Ying Yuan;Yu Geng;Man Zhao;Lian-yun Feng;Xiao-dong Zhang-.IFN-α inhibits HBV transcription and replication by promoting HDAC3-mediated de-2-hydroxyisobutyrylation of histone H4K8 on HBV cccDNA minichromosome in liver)[J].中国药理学报（英文版）,2022(06):1484-1494
A类：
H4K8,restrictor,H4K8hib
B类：
IFN,inhibits,HBV,replication,by,promoting,HDAC3,mediated,hydroxyisobutyrylation,histone,cccDNA,minichromosome,liver,epigenetic,modification,hepatitis,virus,covalently,closed,circular,plays,crucial,role,viral,persistence,Interferon,pivotal,agent,against,However,mechanism,which,modulates,regulation,remains,poorly,understood,this,study,report,that,2b,enhances,lysine,By,screening,acetyltransferases,deacetylases,identified,was,Moreover,found,able,expressing,hepatoma,cells,Then,regulated,depending,domain,system,low,high,were,observed,tissues,from,infected,human,chimeric,mice,levels,significantly,elevated,biopsy,specimens,clinical,patients,consistent,transcriptional,activity,Strikingly,effectively,facilitated,primary,hepatocytes,leading,inhibition,Our,finding,provides,new,insights,into
AB值：
0.370321
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