SIRT7 restricts HBV transcription and replication through catalyzing desuccinylation of histone H3 associated with cccDNA minichromosome.

Chronic HBV infection is a significant public health burden worldwide. HBV cccDNA organized as a minichromosome in nucleus is responsible for viral persistence and is the key obstacle for a cure of chronic hepatitis B. Recent studies suggest cccDNA transcription is epigenetically regulated by histone modifications, especially histone acetylation and methylation. In this study, we identified transcriptionally active histone succinylation (H3K122succ) as a new histone modification on cccDNA minichromosome by using cccDNA ChIP-Seq approach. SIRT7, as a NAD+-dependent histone desuccinylase, could bind to cccDNA through interaction with HBV core protein where it catalysed histone H3K122 desuccinylation. Moreover, SIRT7 acts cooperatively with histone methyltransferase SUV39H1 and SETD2 to induce silencing of HBV transcription through modulation of chromatin structure. Our data improved the understanding of histone modifications of the cccDNA minichromosome, thus transcriptional silencing of cccDNA may represent a novel antiviral strategy for the prevention or treatment of HBV infection. Copyright 2021 The Author(s).