HAT1 signaling confers to assembly and epigenetic regulation of HBV cccDNA minichromosome

Abstract

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.

Histone acetyltransferase 1 is a succinyltransferase for histones and non‐histones and promotes tumorigenesis

“…HAT1 as an acetyltransferase is able to regulate the acetylation of histones and non‐histones (Parthun, 2007; Shahbazian & Grunstein, 2007; Sadler et al , 2015). Our previous study also identified that HAT1‐mediated histone acetylation modulated the assembly and epigenetic regulation of hepatitis B virus covalently closed circular DNA minichromosome (Yang et al , 2019). In this study, we try to identify the novel succinylation function of HAT1 on both histones and non‐histones in tumorigenesis.…”

“…In addition, HAT1 acetylates transcriptional regulator PLZF to modulate the NF‐κB response (Sadler, Suliman et al , 2015). Our previous study also revealed that HAT1‐mediated acetylation contributed to the assembly and epigenetic regulation of hepatitis B virus covalently closed circular DNA minichromosome (Yang, Feng et al , 2019). However, whether HAT1 is able to modulate other PTMs of histones and non‐histones has not been reported.…”

Chronic ethanol consumption and HBV induce abnormal lipid metabolism through HBx/SWELL1/arachidonic acid signaling and activate Tregs in HBV-Tg mice

“…Media were cleared through a 0.45 μm filter and precipitated with 10% PEG8000 and 2.3% NaCl. The precipitates were washed and resuspended with medium at 200-fold concentration 60 , 61 . The HBV DNA was quantified by RT-qPCR.…”

A polypeptide D-TTK001 targeting HBx controls cccDNA against HBV

“…The level of HBV replication is determined by the number of cccDNA molecules and their transcriptional productivity 4 . HBV cccDNA transcription is regulated by epigenetic modifications, including DNA methylation, histone modification, nucleosome remodeling, and RNA-mediated targeting [5][6][7][8] , which are imposed by viral and cellular proteins as well as inflammatory cytokines 9 . HBV X protein (HBx) as a multifunctional HBV protein is crucial for HBV replication, pathogenesis, and hepatocyte carcinogenesis 10 .…”