Epigenetic and epitranscriptomic regulation of viral replication

Abstract

Eukaryotic gene expression is regulated not only by genomic enhancers and promoters, but also by covalent modifications added to both chromatin and RNAs. Whereas cellular gene expression may be either enhanced or inhibited by specific epigenetic modifications deposited on histones (in particular, histone H3), these epigenetic modifications can also repress viral gene expression, potentially functioning as a potent antiviral innate immune response in DNA virus-infected cells. However, viruses have evolved countermeasures that prevent the epigenetic silencing of their genes during lytic replication, and they can also take advantage of epigenetic silencing to establish latent infections. By contrast, the various covalent modifications added to RNAs, termed epitranscriptomic modifications, can positively regulate mRNA translation and/or stability, and both DNA and RNA viruses have evolved to utilize epitranscriptomic modifications as a means to maximize viral gene expression. As a consequence, both chromatin and RNA modifications could serve as novel targets for the development of antivirals. In this Review, we discuss how host epigenetic and epitranscriptomic processes regulate viral gene expression at the levels of chromatin and RNA function, respectively, and explore how viruses modify, avoid or utilize these processes in order to regulate viral gene expression.

Fig. 1. Epigenetic repression of viral DNA.

Upon entry into the cell nucleus, the DNA of many viruses initiates the replication process adjacent to subnuclear structures called pro-myelocytic leukaemia nuclear bodies (PML-NBs). However, PML-NBs are an aggregation site for many heterochromatic repression proteins, which load repressive heterochromatin onto viral DNA that shuts down viral transcription. In the absence of viral de-repression factors, viral episomal DNA lacks active histone marks (shown as green histones with the active marks H3Ac, H4Ac and H3K4me3). a | Several PML-NB components — including PML itself, Sp100, Smc5, Smc6, Daxx and ATRX — are involved in the epigenetic repression of viruses, with the Daxx–ATRX complex having specifically been found to load the histone variant H3.3 bearing repressive marks onto viral DNA, leading to the accumulation of heterochromatic marks and blocked transcription (DNA is shown associated with red histones with the repressive marks H3K9me3 and H3K27me3). b | The innate immune DNA sensor IFI16 drives an alternative mechanism of antiviral epigenetic repression, promoting repressive methylations on histone tail H3K9. c | Specifically for the retrovirus murine leukaemia virus, NP220 and the human silencing hub (HUSH) complex have also been shown to deposit heterochromatic marks on unintegrated viral DNA.

Fig. 2. Viral strategies to avoid epigenetic repression.

Viruses can counteract epigenetic repression in multiple ways in order to enrich for histones bearing active marks (shown as green histones with H3Ac, H4Ac and H3K4me3 marks) and prevent the loading of histones with repressive marks (red histone variant H3.3 bearing the repressive mark H3K9me3). a | The herpes simplex virus 1 (HSV-1) protein VP16 associates with the host factors HCF-1 and Oct-1, with HCF-1 recruiting the host H3K9 demethylases LSD1 and JMJD2 to remove repressive marks, along with the H3K4 methyltransferases Set1 and MLL1 to deposit active marks on viral DNA. b | Several viral proteins target pro-myelocytic leukaemia nuclear body (PML-NB) components in order to avoid epigenetic repression. HSV-1 ICP0 and human cytomegalovirus (HCMV) IE1 induce the degradation of PML and Sp100 (degraded proteins shown in light grey with dotted outlines). Epstein–Barr virus (EBV) BNRF1 disassembles the Daxx–ATRX histone chaperone complex, whereas HCMV pp71 degrades Daxx. Hepatitis B virus (HBV) protein HBx induces the degradation of Smc5 or Smc6. c | HSV-1 can also induce the degradation of IFI16, an alternative antiviral epigenetic repression factor, with ICP0 implicated as being involved in this degradation. d | Retroviruses avoid epigenetic repression by integrating their DNA into host euchromatin, where it can no longer be identified as foreign DNA. MLV, murine leukaemia virus.

Fig. 3. Epitranscriptomic modifications of viral RNA.

The indicated epitranscriptomic marks are N⁶-methyladenosine (m⁶A), 5-methylcytidine (m⁵C), N⁴-acetylcytidine (ac⁴C) and 2ʹO-methylated nucleosides (Nm), deposited respectively by a complex that includes the proteins METTL3, METTL14 and WTAP (among other cofactors), by NSUN2, by nuclear N-acetyltransferase 10 (NAT10) and by FTSJ3. All four of these epitranscriptomic marks have been reported to promote viral replication by affecting different steps in the viral replication cycle, either by upregulating viral mRNA stability or translation, or by preventing the detection of viral RNAs by host RNA-specific innate immunity factors, including RIG-I and MDA5. Of note, it is currently unknown whether RNA modifications have distinct functions when deposited on viral mRNA as opposed to viral RNA genomes, but this remains a possibility.