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.
Highlights
Multicellular organisms possess widely conserved post-transcriptional regulatory mechanisms used to develop and maintain cell and tissue identities
It is clear that miRNAs are important modulators of alternative RNA splicing networks
Disruption of specific miRNA targeting pathways leads to RNA splicing errors that have been described in many types of cancers, neurological disorders, and developmental dysregulation
Summary
Multicellular organisms possess widely conserved post-transcriptional regulatory mechanisms used to develop and maintain cell and tissue identities. MiR-188 was found to target the SRSF7 3 UTR in an acute kidney injury model This interaction led to a decrease in cell viability, potentially induced by the alteration of RNA splicing patterns of anti-apoptotic gene isoforms caused by the lack of SRSF7 [39]. HnRNP A2 is directly targeted by at least three miRNAs. A 2012 study by Sun et al found that hnRNP A2 is repressed by miR-124 and miR-340, while hnRNP A1 is repressed by miR-137 in a luciferase assay [94], which suggests that despite their similarities, hnRNP A1 and hnRNP A2 are regulated by different miRNAs. miRNAs are typically repressors of gene expression, the expression of hnRNP A2, as well as the SFPQ protein (another RNA splicing factor), increased when miR-369 was transfected in mouse adipose-derived mesenchymal stem cells [97]. While an exact mechanism was not established, it is important to note that the 3 UTR of hnRNP A2 but not hnRNP A1 contained a predicted miR-369 binding site, which seems to be able to stabilize hnRNP A2 mRNAs [97,98]
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