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.

Keywords: C. elegans; CELF; PTBP1; PTBP2; Quaking; RBFOX; SR proteins; alternative splicing; cancer; hnRNPs; microRNA; tissue differentiation.

Figure 1

(A) miRNAs bind to target genes within their 3′UTR and repress their translation (Left). Since the pairing between the miRNAs and its target sequence is not perfectly complementary, a single miRNA may target and repress multiple mRNA transcripts (Right). (B) As shown in Tissue A and Tissue B, miRNAs may differentially regulate the abundance of RNA splicing factor proteins (shown as light green circles). Tissue 1 (Left) has a higher dosage of the RNA splicing factor due to a lack of miRNAs available to inhibit their translation. In this specific example, the abundance of splicing factors leads to an intron inclusion event (Isoform A). In contrast, in Tissue 2 (Right), miRNAs that target the RNA splicing factor lower its abundance, interfering with the splicing pattern of target genes. In this specific example, this leads to an intron exclusion event (Isoform B).

Figure 2

In HeLa cells, SRSF1 promotes exon skipping in Ich-1 to produce the pro-apoptotic Ich-1L isoform. However, in HEK 293 cells, SRSF1 promotes the expression of Bcl-xL, the anti-apoptotic isoform of Bcl-x, by favoring a distal 5′ splice site. miR-28 and miR-505 directly target the 3′UTR of SRSF1, and the result induces a shift of the isoform ratios of Ich-1 and Bcl-x.