Epitranscriptomic marks: Emerging modulators of RNA virus gene expression

Abstract

Epitranscriptomics, the study of posttranscriptional chemical moieties placed on RNA, has blossomed in recent years. This is due in part to the emergence of high-throughput detection methods as well as the burst of discoveries showing biological function of select chemical marks. RNA modifications have been shown to affect RNA structure, localization, and functions such as alternative splicing, stabilizing transcripts, nuclear export, cap-dependent and cap-independent translation, microRNA biogenesis and binding, RNA degradation, and immune regulation. As such, the deposition of chemical marks on RNA has the unique capability to spatially and temporally regulate gene expression. The goal of this article is to present the exciting convergence of the epitranscriptomic and virology fields, specifically the deposition and biological impact of N7-methylguanosine, ribose 2'-O-methylation, pseudouridine, inosine, N6-methyladenosine, and 5-methylcytosine epitranscriptomic marks on gene expression of RNA viruses. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.

Keywords: 5-methylcytosine; N6-methyladenosine; N7-methylguanosine; RNA virus; epitranscriptomics; innate immunity; inosine; pseudouridine; ribose 2′-O-methylation.

Figure 1

5′‐Cap on messenger RNA (mRNA). (a) Schematic of N7‐methylguanosine cap attached to nucleotides 1 and 2 of RNA that are 2′‐O‐methylated. (b) Overview of the canonical pathway for installation of Cap 0, Cap 1, and Cap 2 structures at the 5′‐end of an mRNA. The functional significance of the Cap 0, Cap 1, and Cap 2 are shown

Figure 2

Consequences of ribose 2′‐O‐methyl modifications on RNA virus gene expression. Methylation of the 2′‐O‐position on the ribose can occur on all nucleotides and may be deposited by both viral and cellular 2′‐O‐methyltransferases (2′‐O‐MTase). The 2′‐O‐methylation of the penultimate nucleotide of the 5′‐end of the viral RNA limits innate immune sensing, first by masking the recognition of the viral RNA by the cytosolic RNA sensors RIG‐I and Mda5 to prevent transcription of innate immune response genes, and second by preventing the interaction with IFIT proteins which downregulate translation. 2′‐O‐methylated nucleotides (Nm) within viral RNA also function to mask the viral RNA from cytosolic RNA sensors. Deposition of internal 2′‐O‐methyl groups on adenosines (Am) by the viral 2′‐O‐MTase inhibit the elongation of the viral RNA‐dependent RNA polymerase during replication

Figure 3

Editing of Uridine‐to‐Pseudouridine. (a) Pseudouridine synthase (PUS) catalyzes the isomerization of uridine (U) to form 5‐ribosyl uracil or pseudouridine (Ψ). (b) Functional outcomes of U‐to‐Ψ editing

Figure 4

Adenosine‐to‐Inosine editing. (a) ADAR deaminates the C6 position in adenosine (A) to produce inosine (I). (b) A‐to‐I editing in RNA alters RNA metabolism to impact different cellular processes. RdRp, viral RNA‐dependent RNA polymerase

Figure 5

N6‐methyladenosine modification on messenger RNA and functions that are modulated by writer, eraser and reader proteins

Figure 6

Viruses with N6‐methyladenosine (m⁶A) modifications in the viral RNA, and putative functions. Virus families shown include: Flaviviridae (purple) namely hepatitis C virus (HCV), Zika virus (ZIKV), Dengue virus (DENV), West Nile virus (WNV), and yellow fever virus (YFV); Picornaviridae (green) with enterovirus 71 (EV71) and poliovirus; Retroviridae (red) namely human immunodeficiency virus type 1 (HIV‐1), murine leukemia virus (MLV) and Rous sarcoma virus (RSV); and Influenza virus (yellow) within Orthomyxoviridae. vRNA, viral RNA