miRNA-Based Regulation of Alternative RNA Splicing in Metazoans

Abstract

Alternative RNA splicing is an important regulatory process used by genes to increase their diversity. This process is mainly executed by specific classes of RNA binding proteins that act in a dosage-dependent manner to include or exclude selected exons in the final transcripts. While these processes are tightly regulated in cells and tissues, little is known on how the dosage of these factors is achieved and maintained. Several recent studies have suggested that alternative RNA splicing may be in part modulated by microRNAs (miRNAs), which are short, non-coding RNAs (~22 nt in length) that inhibit translation of specific mRNA transcripts. As evidenced in tissues and in diseases, such as cancer and neurological disorders, the dysregulation of miRNA pathways disrupts downstream alternative RNA splicing events by altering the dosage of splicing factors involved in RNA splicing. This attractive model suggests that miRNAs can not only influence the dosage of gene expression at the post-transcriptional level but also indirectly interfere in pre-mRNA splicing at the co-transcriptional level. The purpose of this review is to compile and analyze recent studies on miRNAs modulating alternative RNA splicing factors, and how these events contribute to transcript rearrangements in tissue development and disease.

Non-Coding RNAs: Novel Regulators of Macrophage Homeostasis in Ocular Vascular Diseases

“…miRNAs regulate gene expression by incorporating the RNA-induced silencing complex (RISC) into the 3′ untranslated regions (3′-UTR) of the gene [ 26 ]. miRNAs modulate gene expression by targeting splicing factors (SFs) or RNA-binding proteins (RBPs) [ 27 , 28 ] or specifically targeting alternatively spliced transcripts [ 29 ]. One miRNA can target multiple mRNAs and affect the expression of genes related to functional interacting pathways.…”

Cooperation and Competition of RNA Secondary Structure and RNA–Protein Interactions in the Regulation of Alternative Splicing

“…Changes in RNA structure and the consequent changes in AS can occur due to interaction with other nucleic acids (e.g., with microRNA [ 118 ]), as well as a result of post-transcriptional modifications of the pre-mRNA primary sequence [ 119 ]. Thus, A-to-I editing performed by ADAR proteins regulates AS by changing the nucleotide sequence of the main splicing cis -elements ( Fig.…”

Mechanisms of non-coding RNA-modulated alternative splicing in cancer

“…MiRNAs exert a considerable influence on the modulation of gene expression, mainly by incorporating into the RNA-induced silencing complex (RISC) to the 3’ untranslated regions (3’ UTRs) of genes [ 28 ]. Moreover, several miRNAs have been reported to exert their functions via binding to their targets’ 5’ UTRs or coding regions [ 30 , 31 ]. Functional roles of miRNAs in cancer have been reviewed elsewhere [ 29 ]; herein, we summarize the mechanisms of miRNA-mediated alternative splicing in cancer progression.…”

“…MiRNAs modulate AS by targeting SFs or RNA-binding proteins (RBPs) in cancer [ 26 , 31 ] ( Fig. 1A ).…”