One locus, several functional RNAs—emerging roles of the mechanisms responsible for the sequence variability of microRNAs

Abstract

With the development of modern molecular genetics, the original “one gene-one enzyme” hypothesis has been outdated. For protein coding genes, the discovery of alternative splicing and RNA editing provided the biochemical background for the RNA repertoire of a single locus, which also serves as an important pillar for the enormous protein variability of the genomes. Non-protein coding RNA genes were also revealed to produce several RNA species with distinct functions. The loci of microRNAs (miRNAs), encoding for small endogenous regulatory RNAs, were also found to produce a population of small RNAs, rather than a single defined product. This review aims to present the mechanisms contributing to the astonishing variability of miRNAs revealed by the new sequencing technologies. One important source is the careful balance of arm selection, producing sequentially different 5p- or 3p-miRNAs from the same pre-miRNA, thereby broadening the number of regulated target RNAs and the phenotypic response. In addition, the formation of 5', 3' and polymorphic isomiRs, with variable end and internal sequences also leads to a higher number of targeted sequences, and increases the regulatory output. These miRNA maturation processes, together with other known mechanisms such as RNA editing, further increase the potential outcome of this small RNA pathway. By discussing the subtle mechanisms behind the sequence diversity of miRNAs, this review intends to reveal this engaging aspect of the inherited “RNA world”, how it contributes to the almost infinite molecular variability among living organisms, and how this variability can be exploited to treat human diseases.

Exosomal small RNA profiling in first-trimester maternal blood explores early molecular pathways of preterm preeclampsia

“…A similar question on miRNA arm usage also applies to the hsa-miR-302a or the hsa-miR-144 loci: in both cases, the downregulation of the 3p arm was detected in PE samples ( 88 , 95 ), as compared to our data on the upregulation of the 5p arm ( Table 3 ). Although tissue-specific miRNA arm selection cannot be ruled out ( 47 ), it is intriguing that for both loci, the miRNA database lists the 5p arms as the dominant ones ( https://mirbase.org/ ). However, the differences compared to our study may arise from the comparison of placental tissue results with exosomal results, as well as from the clinical heterogeneity within the PE group ( 81 ).…”

“…miRNAs are shorter, typically between 20-24 nucleotides in length; they associate with the AGO-clade proteins (AGO1-4 in humans), and their effector complexes mostly target mRNAs, initiating their decay and/or inhibiting their translation ( 44 , 45 ). Since a single miRNA molecule can regulate multiple target mRNAs, and vice versa , one mRNA can be regulated by several miRNA species, the functional role of miRNA-containing RISCs can be considered as a complex, post-transcriptional fine-tuning of gene expression ( 46 , 47 ). In contrast, piRNAs are longer, with an average length of 27-35 nucleotides, are 2’-OH methylated at their 3’ end, and associate with the PIWI clade of AGO proteins (PIWIL1-4 in humans) ( 48 ).…”

Multiple Genetic Polymorphisms within microRNA Targets and Homologous microRNA-Binding Sites: Two More Factors Influencing microRNA-Mediated Regulation of Gene Expression

“…Like all RNA molecules, miRNAs undergo posttranscriptional modifications, which may affect their properties [234,260,262,265,266]. Recent studies point to the existence of sequence variants in miRNAs called isomiRs, which differ from the annotated miRNAs by altered sequences due to the various posttranscriptional modifications [267,268].…”

Mechanism and Therapeutic Prospect of miRNAs in Neurodegenerative Diseases

“…Finally, the pre-miRNA is transferred from the nucleus to the cytoplasm by a carrier protein, which is split into short double-stranded RNA of about 22 nucleotides by another nuclease Dicer, and then, this short double-stranded RNA is introduced into the RISC silencing complex containing Ago protein. One mature single-stranded RNA is retained in the RISC silencing complex and is combined to the site of its complementary mRNA to regulate gene expression through base pairing [ 7 ]. There is literature showing that each miRNA may regulate the expression of thousands of proteins, leading to their ability to affect the entire biological process [ 8 ].…”