Abstract
The hepatitis B virus (HBV) infects 257 million people worldwide. HBV infection requires establishment and persistence of covalently closed circular (ccc) DNA, a viral episome, in nucleus. Here, we study cccDNA spatial localization in the 3D host genome by using chromosome conformation capture-based sequencing analysis and fluorescence in situ hybridization (FISH). We show that transcriptionally inactive cccDNA is not randomly distributed in host nucleus. Rather, it is preferentially accumulated at specialized areas, including regions close to chromosome 19 (chr.19). Activation of the cccDNA is apparently associated with its re-localization, from a pre-established heterochromatin hub formed by 5 regions of chr.19 to transcriptionally active regions formed by chr.19 and nearby chromosomes including chr.16, 17, 20, and 22. This active versus inactive positioning at discrete regions of the host genome is primarily controlled by the viral HBx protein and by host factors including the structural maintenance of chromosomes protein 5/6 (SMC5/6) complex.
Highlights
Human hepatitis B virus (HBV) infection remains a global health problem, with more than 250 million people currently living with HBV infection (MacLachlan et al, 2015; Schweitzer et al, 2015)
We further show that this restricted positioning pattern is regulated through the interplay of the host structural maintenance of chromosome (SMC) 5/6 complex and its antagonizing viral factor, the HBV x protein (HBx)
Proximity ligation-based 4C sequencing and fluorescence in situ hybridization (FISH) analysis of the HBV genome Chromosome conformation capture (3C)-based 4C-seq technology is a powerful approach to investigate genome-wide interactions occurring among host chromosomes, and we reasoned that it should be suitable for detecting interactions between pathogen DNA (i.e., DNA viral genomes) and host chromosomes. 4C-seq adopts ‘‘one versus all’’ strategy, in which a single viewpoint is used to screen for all of the regions in the genome that contact a single selected site
Summary
Human hepatitis B virus (HBV) infection remains a global health problem, with more than 250 million people currently living with HBV infection (MacLachlan et al, 2015; Schweitzer et al, 2015). The 42 nm infectious HBV virion enters hepatocytes through a liver-specific bile acids transporter protein (sodium taurocholate cotransporting polypeptide; NTCP) (Yan et al, 2012), followed by capsid uncoating and nuclear transport of the viral DNA genome that is a relaxed circular DNA. The episomal HBV cccDNA, usually conceptualized as a mini-chromosome, is the template for transcription of all HBV viral RNAs, including the 3.5 kb pregenome (pg) RNA and preC mRNA, 2.4 kb preS mRNA, 2.1 kb S mRNA, and 0.7 kb HBx mRNA. Despite the advances in understanding, our knowledge about the biology of cccDNA is still fragmented
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