KAT2A Promotes Hepatitis B Virus Transcription and Replication Through Epigenetic Regulation of cccDNA Minichromosome

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.

Co-Transcriptional Regulation of HBV Replication: RNA Quality Also Matters

“…Other PTMs of cccDNA-bound histones have been identified and regulate cccDNA transcriptional activity. Indeed, succinylation of H3K122 catalyzed by lysine acetyltransferase 2A (KAT2A) and removed by sirtuin 7 (SIRT7) is associated with transcriptional activation [ 58 , 59 ]. Conversely, trimethylation of H3K9 or H3K27 catalyzed by SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) and the polycomb repressive complex 2 (PRC2), respectively, are associated with transcriptional silencing of cccDNA [ 54 , 60 , 61 ].…”

“… Regulators of HBV cccDNA transcription. Examples of host or viral factors activating (green) or silencing (red) cccDNA transcriptional activity associated with an active (green nucleosomes) or a silent (red nucleosomes) chromatin [ 37 , 38 , 39 , 40 , 43 , 47 , 48 , 49 , 50 , 52 , 53 , 54 , 56 , 57 , 58 , 59 , 60 , 62 , 63 , 65 , 66 , 67 , 68 , 70 , 74 , 75 , 76 , 77 ]. The image was created using Biorender.com.…”

Post-translational modulation of cell signalling through protein succinylation

“…HBV is a small DNA virus that targets hepatocytes [ 119 ] and covalently closed circular DNA (cccDNA) serves as a template for HBV replication by hijacking the host’s transcriptional machinery [ 120 ]. It has been discovered that cccDNA succinylation upregulated HBV transcriptional activity [ 118 ]. KAT2A is recruited to the minichromosome and succinylates H3 K79 to facilitate HBV replication [ 116 ].…”

Post-Translational Modifications by Lipid Metabolites during the DNA Damage Response and Their Role in Cancer

“…Lysine succinyltransferases (KSTases) are responsible for catalyzing lysine succinylation. For example, lysine acetyltransferase 2A (KAT2A) is known to succinylate H3K79 and to promote tumor cell proliferation [ 133 ]. Succinyl CoA is also known to be produced when tyrosine 645 (Y645) in KAT2A interacts with α-ketoglutarate dehydrogenase complex (a-KGDH) in the nucleus [ 134 ].…”