Abstract
Hepatitis B virus (HBV) infection remains a major health problem worldwide. Sufficient maintenance of the HBV covalently closed circular DNA (cccDNA), which serves as a template for HBV transcription, is responsible for the failure of antiviral therapies. While accumulating evidence suggests that cccDNA transcription is regulated by epigenetic machinery, particularly the acetylation and methylation of cccDNA-bound histone 3 (H3) and histone 4 (H4), the potential contributions of histone succinylation and related host factors remain obscured. Here, by screening a series of succinyltransferases and desuccinylases, we identified KAT2A as an important host factor of HBV transcription and replication. By using HBV-infected cells and mouse models with HBV infection, KAT2A was found to affect the transcriptional activity of cccDNA but did not affect cccDNA production. Mechanism studies showed that KAT2A is mainly located in the nucleus and could bind to cccDNA through interaction with HBV core protein (HBc). Moreover, we confirmed histone H3K79 succinylation (H3K79succ) as a histone modification on cccDNA minichromosome by using the cccDNA ChIP-Seq approach. Importantly, KAT2A silencing specifically reduced the level of cccDNA-bound succinylated H3K79. In conclusion, KAT2A promotes HBV transcription and replication through epigenetic machinery, and our findings may provide new insight into the treatment of HBV infection.
Highlights
Hepatitis B virus (HBV) infection remains a major global public health issue despite the availability of an effective vaccine and antiviral drugs that prevent HBV infection and arrest disease progression
Upon entry into a hepatocyte, relaxed-circular partially double-stranded DNA (rcDNA) in the HBV virion is delivered into the nucleus and converted into covalently closed circular DNA, which serves as a transcription template for all viral transcripts, including the 3.5-kb precore RNA and pregenomic RNA, the 2.4-kb and 2.1kb surface mRNAs, and a 0.7-kb X mRNA (Block et al, 2007). pgRNA is a template for viral reverse transcription and translation into viral polymerase (Pol) and HBV core protein (HBc) (Jones and Hu, 2013)
Multiple pieces of evidence have revealed the critical role of histone modification in regulating the transcription of closed circular DNA (cccDNA), the acetylation and methylation of cccDNA-bound histone 3 (H3) and histone 4 (H4) (Zhang et al, 2017, p. 5; Ren et al, 2018, p. 3)
Summary
Hepatitis B virus (HBV) infection remains a major global public health issue despite the availability of an effective vaccine and antiviral drugs that prevent HBV infection and arrest disease progression. Recent global hepatitis report estimates indicate 257 million people living with chronic HBV infection Upon entry into a hepatocyte, rcDNA in the HBV virion is delivered into the nucleus and converted into covalently closed circular DNA (cccDNA), which serves as a transcription template for all viral transcripts, including the 3.5-kb precore RNA (pcRNA) and pregenomic RNA (pgRNA), the 2.4-kb and 2.1kb surface mRNAs, and a 0.7-kb X mRNA (Block et al, 2007). HBV cccDNA is the key intermediate in the viral life cycle, which is responsible for the persistence of the infection during the natural course of chronic infection and prolonged antiviral treatment (Hong et al, 2017). Targeting cccDNA represents the key approach to cure HBV infection
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