Interplay of microRNAs, transcription factors and target genes: linking dynamic expression changes to function

Abstract

MicroRNAs (miRNAs) are ubiquitously expressed small non-coding RNAs that, in most cases, negatively regulate gene expression at the post-transcriptional level. miRNAs are involved in fine-tuning fundamental cellular processes such as proliferation, cell death and cell cycle control and are believed to confer robustness to biological responses. Here, we investigated simultaneously the transcriptional changes of miRNA and mRNA expression levels over time after activation of the Janus kinase/Signal transducer and activator of transcription (Jak/STAT) pathway by interferon-γ stimulation of melanoma cells. To examine global miRNA and mRNA expression patterns, time-series microarray data were analysed. We observed delayed responses of miRNAs (after 24–48 h) with respect to mRNAs (12–24 h) and identified biological functions involved at each step of the cellular response. Inference of the upstream regulators allowed for identification of transcriptional regulators involved in cellular reactions to interferon-γ stimulation. Linking expression profiles of transcriptional regulators and miRNAs with their annotated functions, we demonstrate the dynamic interplay of miRNAs and upstream regulators with biological functions. Finally, our data revealed network motifs in the form of feed-forward loops involving transcriptional regulators, mRNAs and miRNAs. Additional information obtained from integrating time-series mRNA and miRNA data may represent an important step towards understanding the regulatory principles of gene expression.

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“…Wang et al (2010) extracted 243 out of 5000 reports in the literature on TF-miRNA relationships in human and made a database called TransmiR. Nazarov et al (2013) investigated simultaneously the transcriptional changes of miRNA and mRNA expression levels in microarray time-series data derived from Jak/STAT activated melanoma cells and observed the delayed response of miRNAs with respect to mRNAs. They also extracted network FFL motifs involving transcriptional regulators, mRNAs and miRNAs.…”

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“…bioinformatics.lu/CoExpress), could be chosen to perform interactive detection of correlated profiles in large expression data sets. Finally, a luciferase reporter assay will confirm associations between the miRNA and its targets (56). Publications of validated miR-target correlations are recorded in TarBase.…”