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

Here, 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 CDS 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 which sense disruptions to miRNA levels. These findings indicate that while bidirectional regulation of miR-1271-5p results in substantial remodelling 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. Overall design: Examination of changes in mRNA expression and translation in neuronally differentiated SH-SY5Y cells after overexpression or knockdown of miR-1271-5p