PRMT5 restricts hepatitis B virus replication through epigenetic repression of covalently closed circular DNA transcription and interference with pregenomic RNA encapsidation

Abstract

PRMT5 restricts HBV replication through a two-part mechanism including epigenetic suppression of cccDNA transcription and interference with pregenomic RNA encapsidation; these findings improve the understanding of epigenetic regulation of HBV transcription and host-HBV interaction, thus providing new insights into targeted therapeutic intervention. (Hepatology 2017;66:398-415).

Epigenetic regulation of hepatitis B virus covalently closed circular DNA: Implications for epigenetic therapy against chronic hepatitis B

“…A growing body of evidence suggests that histone modifications on cccDNA regulate the viral transcription. The HBc and HBx proteins, H3 and H4 histones, cellular transcription factors (CREB [cAMP response element‐binding protein], activating transcription factor, YY1 [Yin Yang 1], signal transducer and activator of transcription [STAT] 1, and STAT2), and chromatin modification enzymes (PCAF [p300/CBP‐associated factor]/GCN5 [general control nonderepressible 5], p300/CBP [CREB‐binding protein], HDAC1, SIRT1 [sirtuin 1], protein arginine methyltransferase [PRMT] 1, PRMT5, and EZH2 [enhancer of zeste homolog 2]) have been shown to be associated with cccDNA by using chromatin immunoprecipitation assays (Fig. ).…”

“…EZH2 is a subunit of PRC2 and has the KMT activity on H3K27. Interestingly, a recent study showed that knockdown of EZH2 resulted in up‐regulation of HBeAg and HBsAg, indicating a repressive function of EZH2 on HBV gene expression . H3K122ac is enriched at genetic elements associated with transcriptionally active genomes in vivo and is catalyzed by the transcriptional coactivator, p300/CBP .…”

“…According to the RNA interference–based screening of known histone methyltransferases (SUV39H [suppressor of variegation 3‐9 homolog], G9a, EZH2, and PRMT5) and demethylases (lysine‐specific demethylase 1, KDM5A, and KDM2A), Zhang et al revealed that the PRMT5‐mediated histone H4 dimethyl Arg3 symmetric (H4R3me2s) repressed cccDNA transcription. In addition, PRMT5‐mediated H4R3me2s interacted with HBc and the Brg1‐based hSWI/SNF chromatin remodeler, which accounted for the reduced binding of RNA polymerase II to cccDNA …”

Host functions used by hepatitis B virus to complete its life cycle: Implications for developing host-targeting agents to treat chronic hepatitis B

“…cccDNA is complexed with cellular histone and non-histone proteins, assembling in to chromatin like structures, as has been called a mini-chromosome (Bock et al, 1994, 2001; Newbold et al, 1995). Enrichment of host RNA pol II on cccDNA has been reported to be associated with active posttranscriptional modifications (PTMs) on ccc-DNA bound histone (Riviere et al, 2015; Zhang et al, 2017). …”

“…There is active co-recruitment of cellular histone acetyltransferases-p300/CBP and PCAF/GCN5- and the histone deacetylases (HDAC1 and hSirt1) and polycomb repressor complex (EZH2 and YY1) in vivo and in vitro onto cccDNA that correlate with high and low viral replication, respectively (Belloni et al, 2009, 2012). In other attempts to study the histone methylation status of cccDNA and regulation of its transcription, PRMT5 (protein methyltransferase 5) has been shown to induce a symmetric di-methylation of H4R3 on cccDNA and regulate the binding of host pol II and host Brg1-based hSW1/SNF chromatin remodeler contributing to the transcriptional repression RNA of cccDNA (Zhang et al, 2017); in addition, hSirt3 was found to restrict HBV cccDNA transcription by acting cooperatively with histone methyltransferase SUV39H1 to decrease the recruitment of SETD1A, leading to a marked increase of H3K9me3 and a decrease of H3K4me3 on cccDNA (Ren et al, 2018). …”