miRNA Nomenclature: A View Incorporating Genetic Origins, Biosynthetic Pathways, and Sequence Variants

Abstract

High-throughput sequencing of miRNAs has revealed the diversity and variability of mature and functional short noncoding RNAs, including their genomic origins, biogenesis pathways, sequence variability, and newly identified products such as miRNA-offset RNAs (moRs). Here we review known cases of alternative mature miRNA-like RNA fragments and propose a revised definition of miRNAs to encompass this diversity. We then review nomenclature guidelines for miRNAs and propose to extend nomenclature conventions to align with those for protein-coding genes established by international consortia. Finally, we suggest a system to encompass the full complexity of sequence variations (i.e., isomiRs) in the analysis of small RNA sequencing experiments.

Keywords: isomiR; loop-origin miRNAs; miRNA cluster; miRNA-seq; moR; noncoding RNA.

Figure 1. Diverse genetic origins and biogenesis pathways leading to functional microRNAs

Many different types of non-coding RNA genes (e.g. canonical miRNAs, snoRNAs, lncRNAs, tRNAs) are transcribed, cleaved into precursor microRNAs (pre-MiRNAs) and eventually processed into miRNA duplexes from which one strand loads into an Argonaute protein (AGO) and represses mRNA translation through the RNA-Induced Silencing Complex (RISC). Canonical miRNAs, lncRNA and AGO2-processed miRNAs (i.e. MiR451) depend on DROSHA and DGCR8 for processing of the primary miRNA transcript into the precursor miRNA. miRtron precursors, on the other hand, are produced by the messenger RNA splicing machinery into simple miRtrons, in which intron splicing defines both ends of the hairpin, or tailed miRtrons, which contain templated regions 5′ or 3′ to a splice-derived terminal intron. snoRNA, shRNA, inverted-repeat derived endo-siRNA, vaultRNA and Y_RNA appear to be DROSHA-independent and are transcribed directly into an RNA fragment displaying the characteristics of a precursor miRNA. In some cases, tRNAs can also be cleaved to produce small RNA fragments by folding into an alternative secondary structure that shows characteristics of a precursor-miRNA. Dicer processes most precursor miRNAs (i.e. canonical miRNA, miRtron, some snoRNA, lncRNA, tRNA, shRNA, inverted-repeat derived endo-siRNA, and vaultRNA) to give rise to a miRNA duplex. Some snoRNA-derived miRNAs and Y_RNA-derived short fragments appear to be Dicer-independent but the enzyme producing the short fragments remains currently unknown. Cis- and trans-derived endo-siRNAs are by nature transcribed directly into a miRNA duplex. miRNA duplexes are then unwound and one side of the duplex, the mature miRNA, is loaded into an AGO protein that drives the assembly of the RISC and the repression of protein translation of the targeted transcript. An AGO2-processed miRNA is an exception to this biogenesis step because it is Dicer-independent and the catalytic activity of the AGO2 protein produces the mature miRNA. Functional experiments are critical to separate true microRNAs from degradation products of these other RNA types.