miRNAs are small single-stranded RNA species of approximately 20–24 bases in length that regulate gene expression through post transcriptional mechanisms. Expression of miRNAs is thought to be ubiquitous among multicellular eukaryotes. In addition to eukaryotic miRNAs, more than 100 viral miRNAs have been identified, almost all of which are expressed by herpesviruses. Targets for the majority of viral miRNAs are currently unknown due to the difficulty involved in identifying novel target transcripts. This remains one of the major challenges in elucidating the function of miRNAs. However, recent reports have begun to elucidate the various roles of viral miRNAs. These include blocking apoptosis, immune evasion and regulation of virus replication through targeting of both cellular and virus gene expression.
Regulation of gene expression is as important as the genes themselves in determining the diverse array of living creatures we see in nature. Recently, scientists have discovered a whole new level of gene regulation through the actions of small molecules called microRNAs (miRNAs). It is currently thought that miRNAs regulate gene expression primarily through binding to target sites within the 3′ untranslated region (UTR) of mRNAs. This paper identifies a population of cellular genes that are targeted by a virally-encoded miRNA. Many of the genes are related to cell cycle control, suggesting that the viral miRNA is targeting genes within a related pathway. In contrast to most miRNAs, this miRNA inhibits gene expression through binding to target sites within the 5′ UTRs, suggesting that viral miRNAs may target genes through mechanisms divergent from cellular miRNAs.
A Viral microRNA Down-Regulates Multiple Cell Cycle Genes through mRNA 5′ UTRs. (2010) PLoS Pathog 6(6): e1000967. doi:10.1371/journal.ppat.1000967
Global gene expression data combined with bioinformatic analysis provides strong evidence that mammalian miRNAs mediate repression of gene expression primarily through binding sites within the 3′ untranslated region (UTR). Using RNA induced silencing complex immunoprecipitation (RISC-IP) techniques we have identified multiple cellular targets for a human cytomegalovirus (HCMV) miRNA, miR-US25-1. Strikingly, this miRNA binds target sites primarily within 5′UTRs, mediating significant reduction in gene expression. Intriguingly, many of the genes targeted by miR-US25-1 are associated with cell cycle control, including cyclin E2, BRCC3, EID1, MAPRE2, and CD147, suggesting that miR-US25-1 is targeting genes within a related pathway. Deletion of miR-US25-1 from HCMV results in over expression of cyclin E2 in the context of viral infection. Our studies demonstrate that a viral miRNA mediates translational repression of multiple cellular genes by targeting mRNA 5′UTRs.