Rationale: Hepatitis B virus (HBV) is a leading cause of liver diseases. HBV covalently closed circular DNA (cccDNA) is a critical obstacle of complete elimination by anti-HBV therapy. HBV cccDNA accumulates in nucleus as a chromatin-like cccDNA minichromosome assembled by histones and non-histones. However, the underlying mechanism of modulation of cccDNA minichromosome in hepatocytes is poorly understood.Methods: A human liver-chimeric mouse model was established. The cccDNA-ChIP, Southern blot analysis, confocal assays, RIP assays and RNA pull-down assays, et al. were performed to assess the mechanism of assembly and epigenetic regulation of cccDNA minichromosome in human liver-chimeric mouse model, human primary hepatocytes (PHH), dHepaRG, HepG2-NTCP cell lines and clinical liver tissues.Results: Importantly, the expression levels of HAT1, CAF-1 and lncRNA HULC were significantly elevated in the liver from HBV-infected human liver-chimeric mice. Strikingly, the depletion of HAT1 reduced HBV replication and cccDNA accumulation, and impaired the assembly of histone H3/H4 and the deposition of HBx and p300 onto cccDNA to form cccDNA minichromosome in the cells. Mechanically, chromatin assembly factor-1 (CAF-1) was involved in the events. Interestingly, HAT1 modified the acetylation of histone H3K27/H4K5/H4K12 on cccDNA minichromosome. Moreover, lncRNA HULC-scaffold HAT1/HULC/HBc complex was responsible for the modification on cccDNA minichromosome. Additionally, HBV activated HAT1 through HBx-co-activated transcriptional factor Sp1 in a positive feedback manner.Conclusion: HAT1 signaling contributes to assembly and epigenetic regulation of HBV cccDNA minichromosome.

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Hepatocellular carcinoma (HCC) is often associated with pre-existing chronic liver pathologies of different origin infections of hepatitis B virus (HBV) and hepatitis C virus. Clinically, the diagnosis and therapy for HCC are very important for the prognosis of patients. However, current methods for HCC diagnosis and therapy have no an optimal accuracy due to the tumor heterogeneity and the frequent late diagnosis. This review summarizes the new advances in molecular diagnosis and therapy of HCC, based on the recent novel biomarkers and new therapeutic strategies for HCC, including alpha-fetoprotein-L3, glypican-3, heat shock protein 90, dickkopf WNT signaling pathway inhibitor 1, paraoxonase 1, highly up-regulated in liver cancer. Moreover, epigenetic regulation, signal pathway, cellular and molecular targets for the immunotherapy, tumor microenviroment and genome sequencing analysis may serve as the molecular expression signatures in clinical practice. For promising new treatment strategy of HCC, targeting molecular therapy based on the restoration of tumor suppressor genes lost and inhibition of oncogenic genes is attractive. The new clinical trials for other molecular-targeted agents, including pembrolizumab, nivolumab, tivantinib, lenvatinib, cabozantinib, and ramucirumab, are ongoing in clinic. Interestingly, anti-HBV drugs display an amazing therapy for HBV-related HCC. In future, the global determination of more biomarkers may provide new insights into the diagnosis of HCC. More importantly, the diagnostic markers should be used to trace patient's follow-up disease progression, guiding doctors to judge and prescribe drugs for status of an illness, prognosis and other processes.