Cooperative gene regulation by microRNA pairs and their identification using a computational workflow

Abstract

MicroRNAs (miRNAs) are an integral part of gene regulation at the post-transcriptional level. Recently, it has been shown that pairs of miRNAs can repress the translation of a target mRNA in a cooperative manner, which leads to an enhanced effectiveness and specificity in target repression. However, it remains unclear which miRNA pairs can synergize and which genes are target of cooperative miRNA regulation. In this paper, we present a computational workflow for the prediction and analysis of cooperating miRNAs and their mutual target genes, which we refer to as RNA triplexes. The workflow integrates methods of miRNA target prediction; triplex structure analysis; molecular dynamics simulations and mathematical modeling for a reliable prediction of functional RNA triplexes and target repression efficiency. In a case study we analyzed the human genome and identified several thousand targets of cooperative gene regulation. Our results suggest that miRNA cooperativity is a frequent mechanism for an enhanced target repression by pairs of miRNAs facilitating distinctive and fine-tuned target gene expression patterns. Human RNA triplexes predicted and characterized in this study are organized in a web resource at www.sbi.uni-rostock.de/triplexrna/.

Transcription factor Sox10 regulates oligodendroglial Sox9 levels via microRNAs

“…We also checked for potential cooperativity between miR335 and miR338 on Sox9 transcripts in man and mouse by retrieving information from the TriplexRNA database (Schmitz et al, 2014). Again, we did not find any evidence for cooperativity and therefore assume additive repression of the target.…”

Identification and validation of microRNAs directly regulating the UDP-glucuronosyltransferase 1A subfamily enzymes by a functional genomics approach

“…Importantly, it is unclear whether miRNAs other than miR-491–3p are involved in the direct regulation UGT1A expression. While most miRNAs have a quantitatively small (usually less than 2-fold) effect on gene expression, many genes are regulated by multiple miRNAs resulting in an additive or, in some instances, a synergistic effect [18]. Furthermore, the UGT1A 3’-UTR contains three common linked SNPs (rs10929303, rs1042640, and rs8330), which have the potential to either disrupt or enhance miRNA binding [12].…”

Angiotensin II‐induced micro RNA‐21 culprit for non‐small‐cell lung adenocarcinoma

“…One of the important reasons is that a series of miRNAs are observed upregulated or downregulated coordinately generally in tumors (Dvinge et al, ; Landgraf et al, ; Lu et al, ). They can target the same genes, and may possess cooperative oncogenic or carcinostatic functions by forming miRNA pairs (Mavrakis et al, ; Schmitz et al, ) or modulating transcription factor (TF) expression (Gupta et al, ; Pradhan, Singhvi, Dubey, Gupta, & Dua, ; Rahman et al, ; Sun, Gong, Purow, & Zhao, ). Although little is currently known about the specific targets and biological functions of miRNA molecules thus far, it is evident that miRNA plays a crucial role in the regulation of gene expression controlling diverse cellular and metabolic pathways (Gupta et al, ; Meenu Mehta et al, ).…”

“…One of the important reasons is that a series of miRNAs are observed upregulated or downregulated coordinately generally in tumors (Dvinge et al, 2013;Landgraf et al, 2007;Lu et al, 2005). They can target the same genes, and may possess cooperative oncogenic or carcinostatic functions by forming miRNA pairs (Mavrakis et al, 2011;Schmitz et al, 2014) or modulating transcription factor (TF) expression Pradhan, Singhvi, Dubey, Gupta, & Dua, 2019;Rahman et al, 2012;Sun, Gong, Purow, & Zhao, 2012).…”