Abstract
MicroRNA (miRNA) and endogenous small interfering RNA (endo-siRNA) are two essential classes of small noncoding RNAs (sncRNAs) in eukaryotes. The class of miRNA is diverse and there exist noncanonical miRNAs that bypass the canonical miRNA biogenesis pathway. In order to identify noncanonical miRNAs and endo-siRNAs responding to virus infection and study their potential function, we sequenced small-RNA species from cells lytically infected with murine gammaherpesvirus 68 (MHV68). In addition to three novel canonical miRNAs in mouse, two antisense miRNAs in virus and 25 novel noncanonical miRNAs, including miRNAs derived from transfer RNAs, small nucleolar RNAs and introns, in the host were identified. These noncanonical miRNAs exhibited features distinct from that of canonical miRNAs in lengths of hairpins, base pairings and first nucleotide preference. Many of the novel miRNAs are conserved in mammals. Besides several known murine endo-siRNAs detected by the sequencing profiling, a novel locus in the mouse genome was identified to produce endo-siRNAs. This novel endo-siRNA locus is comprised of two tandem inverted B4 short interspersed nuclear elements (SINEs). Unexpectedly, the SINE-derived endo-siRNAs were found in a variety of sequencing data and virus-infected cells. Moreover, a murine miRNA was up-regulated more than 35 fold in infected than in mock-treated cells. The putative targets of the viral and the up-regulated murine miRNAs were potentially involved in processes of gene transcription and protein phosphorylation, and localized to membranes, suggesting their potential role in manipulating the host basal immune system during lytic infection. Our results extended the number of noncanonical miRNAs in mammals and shed new light on their potential functions of lytic infection of MHV68.
Highlights
IntroductionMicroRNAs (miRNAs) are ,22-nt small noncoding RNAs (sncRNAs) that are encoded in virus, plants and animals [1,2,3]
MicroRNAs are,22-nt small noncoding RNAs that are encoded in virus, plants and animals [1,2,3]
Of the reads mapped to murine gammaherpesvirus 68 (MHV68), 241,683 (88.1% of the total) came from the known MHV68 pre-miRNA sequences; of the reads mapped to the host genome, 19,701,917 (92.2% of the total) were from the known murine pre-miRNA sequences
Summary
MicroRNAs (miRNAs) are ,22-nt small noncoding RNAs (sncRNAs) that are encoded in virus, plants and animals [1,2,3]. They play essential regulatory roles in a wide variety of cellular processes. The nuclear processing of primiRNAs by Drosha and double-strand RNA (dsRNA) binding protein Dgcr releases hairpin-structured precursors (pre-miRNAs). There, Dicer cleaves the pre-miRNAs to release ,22-nt RNA duplexes with ,2-nt 39 overhangs. The miRNA guides the RISC to its perfectly or partially complementary binding sites, which are normally in the 39 untranslated regions (UTRs) of targeted transcripts in animal organisms, to exert its regulatory function. The binding preference often depends on the miRNA’s 2- to 8-nt sequence from its 59 end, the so-called seed region of the miRNA [5]
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