Abstract
With about 350 million people chronically infected around the world hepatitis B is a major health problem. Template for progeny HBV synthesis is the viral genome, organized as a minichromosome (cccDNA) inside the hepatocyte nucleus. How viral cccDNA gene expression is regulated by its chromatin structure; more importantly, how the modulation of this structure impacts on viral gene expression remains elusive. Here, we found that the enzyme SetDB1 contributes to setting up a repressed cccDNA chromatin state. This repressive state is activated by the histone lysine demethylase-1 (LSD1). Consistently, inhibiting or reducing LSD1 levels led to repression of viral gene expression. This correlates with the transcriptionally repressive mark H3K9 methylation and reduction on the activating marks H3 acetylation and H3K4 methylation on viral promoters. Investigating the importance of viral proteins we found that LSD1 recruitment to viral promoters was dependent on the viral transactivator protein HBx. Moreover, the histone methyltransferase Set1A and HBx are simultaneously bound to the core promoter, and Set1A expression correlates with cccDNA H3K4 methylation. Our results shed light on the mechanisms of HBV regulation mediated by the cccDNA chromatin structure, offering new therapeutic targets to develop drugs for the treatment of chronically infected HBV patients.
Highlights
HBV is an enveloped pararetrovirus containing a partially double stranded DNA genome, which is surrounded by the viral capsid
Given that the herpes virus regulates its reactivation from latency in part by recruiting lysine-specific demethylase-1 (LSD1) to demethylate H3K9me[2] on repressed immediate early herpes viral promoter genes[23,24], and that histone H3 bound to the HBV closed circular double-strand DNA (cccDNA) is methylated at residue K9 (Fig. 1A), we investigated the effect of LSD1 on HBV replication
Despite the knowledge that has been gained about the impact of chromatin structure on gene expression, only a few reports have investigated how histone modification changes on the cccDNA minichromosome influence HBV gene expression[11,14,15,19,20]
Summary
HBV is an enveloped pararetrovirus containing a partially double stranded DNA genome (relaxed circular DNA, rcDNA), which is surrounded by the viral capsid. Recent reports revealed that the cccDNA chromatin structure regulates the HBV replication and transcription[9,10,11,12,13,14,15], utilizing host mechanisms that control cellular genome expression[16,17]. The viral protein HBx plays a pivotal role in HBV viral transcription On one hand it regulates the degradation of the structural maintenance of chromosomes (SMC) complex Smc5/6 avoiding its binding and repression of viral cccDNA18. In the presence of viral protein HBx the cccDNA forms an active chromatin state, with reduced levels of H3K9me[20]. HBx recruits the enzyme Set1A to viral promoters to trimethylate H3K4, a mark associated with transcriptional activation, helping to establish an active viral chromatin state
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