Comparing miRNA structure of mirtrons and non-mirtrons

Abstract

BackgroundMicroRNAs proceeds through the different canonical and non-canonical pathways; the most frequent of the non-canonical ones is the splicing-dependent biogenesis of mirtrons. We compare the mirtrons and non-mirtrons of human and mouse to explore how their maturation appears in the precursor structure around the miRNA.ResultsWe found the coherence of the overhang lengths what indicates the dependence between the cleavage sites. To explain this dependence we suggest the 2-lever model of the Dicer structure that couples the imprecisions in Drosha and Dicer. Considering the secondary structure of all animal pre-miRNAs we confirmed that single-stranded nucleotides tend to be located near the miRNA boundaries and in its center and are characterized by a higher mutation rate. The 5′ end of the canonical 5′ miRNA approaches the nearest single-stranded nucleotides what suggests the extension of the loop-counting rule from the Dicer to the Drosha cleavage site. A typical structure of the annotated mirtron pre-miRNAs differs from the canonical pre-miRNA structure and possesses the 1- and 2 nt hanging ends at the hairpin base. Together with the excessive variability of the mirtron Dicer cleavage site (that could be partially explained by guanine at its ends inherited from splicing) this is one more evidence for the 2-lever model. In contrast with the canonical miRNAs the mirtrons have higher snp densities and their pre-miRNAs are inversely associated with diseases. Therefore we supported the view that mirtrons are under positive selection while canonical miRNAs are under negative one and we suggested that mirtrons are an intrinsic source of silencing variability which produces the disease-promoting variants. Finally, we considered the interference of the pre-miRNA structure and the U2snRNA:pre-mRNA basepairing. We analyzed the location of the branchpoints and found that mirtron structure tends to expose the branchpoint site what suggests that the mirtrons can readily evolve from occasional hairpins in the immediate neighbourhood of the 3′ splice site.ConclusionThe miRNA biogenesis manifests itself in the footprints of the secondary structure. Close inspection of these structural properties can help to uncover new pathways of miRNA biogenesis and to refine the known miRNA data, in particular, new non-canonical miRNAs may be predicted or the known miRNAs can be re-classified.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-4473-8) contains supplementary material, which is available to authorized users.

Erratum to: How Animal miRNAs Structure Influences Their Biogenesis

“…In many mirtrons without hanging tails and in mirtrons with a hanging 3'-tail (so-called "3'-tailed mirtrons"), the guanine located at the boundary of the intron and exon is additionally removed from the 5'end [85]. This guanine removal may be an additional mechanism for increasing the accuracy of the pre-miRNA cleavage by RNase III Dicer [87].…”

“…The typical structure of mirtron precursors contains feature imprints of their biogenesis and differs from the structure of canonical pre-miRNAs: the overhanging end at the base of the hairpin often consists of one rather than double nucleotides [87]. Compared to canonical miRNAs, mirtrons have a higher density of single nucleotide polymorphisms (SNPs), and the SNPs themself are inversely associated with diseases.…”

“…Mirtrons are probably under positive (driving) selection, while most of the canonical miRNAs are under negative (stabilizing) one; mirtrons can be an inherent source of variability that contributes to disease. It is interesting that the splicing branchpoint nucleotide is often located exactly in that place so as not to be shielded by the structure of the mirtron pre-cursor [87]. In this way, mirtrons can be easily created from random hairpins of a suitable size near the 3'splice site.…”

“…Nucleotide substitutions are more often observed in the center of miRNA and in the vicinity of its ends in the precursor; the regions responsible for addressing miRNA, the so-called seed (positions 2-8 of miRNA) and additional seed (positions 13-16), are more conservative [96]. These two regions are also characterized by the least presence of loops [87,96]: a similar relationship between the intensity of mutagenesis and the secondary structure is characteristic of structural RNAs, for example, tRNA [97].…”

MiRNA seed shifting: origin and functional implications

“…During the evolution the accumulated mutations in the pri-/pre-/miRNA change the miRNA boundaries (including "seed" location), sequence and secondary structure of the precursor. Other reasons of miRNA end heterogeneity are an inaccuracy of processing by the RNase proteins or by the splicing, their predisposition to the precursor sequence and structure and possible interconnection between Dicer cleavage errors and the length of the pre-miRNA hanging ends [1,3]. The considered changes can lead to the new biological functions of miRNA and diverse levels of miRNA expression.…”