Characterising the Transcriptional and Translational Impact of the Schizophrenia-Associated miR-1271-5p in Neuronal Cells

Abstract

MicroRNA (miRNA) coordinate complex gene expression networks in cells that are vital to support highly specialised morphology and cytoarchitecture. Neurons express a rich array of miRNA, including many that are specific or enriched, which have important functions in this context and implications for neurological conditions. While the neurological function of a number of brain-derived miRNAs have been examined thoroughly, the mechanistic basis of many remain obscure. In this case, we investigated the transcriptome-wide impact of schizophrenia-associated miR-1271-5p in response to bidirectional modulation. Alteration of miR-1271-5p induced considerable changes to mRNA abundance and translation, which spanned a diverse range of cellular functions, including directly targeted genes strongly associated with cytoskeletal dynamics and cellular junctions. Mechanistic analyses additionally revealed that upregulation of miR-1271-5p predominantly repressed mRNAs through destabilisation, wherein 3'UTR and coding sequence binding sites exhibited similar efficacy. Knockdown, however, produced no discernible trend in target gene expression and strikingly resulted in increased expression of the highly conserved miR-96-5p, which shares an identical seed region with miR-1271-5p, suggesting the presence of feedback mechanisms that sense disruptions to miRNA levels. These findings indicate that, while bidirectional regulation of miR-1271-5p results in substantial remodeling of the neuronal transcriptome, these effects are not inverse in nature. In addition, we provide further support for the idea that destabilisation of mRNA is the predominant mechanism by which miRNAs regulate complementary mRNAs.