A Systematic Screen Reveals MicroRNA Clusters That Significantly Regulate Four Major Signaling Pathways

Abstract

MicroRNAs (miRNAs) are encoded in the genome as individual miRNA genes or as gene clusters transcribed as polycistronic units. About 50% of all miRNAs are estimated to be co-expressed with neighboring miRNAs. Recent studies have begun to illuminate the importance of the clustering of miRNAs from an evolutionary, as well as a functional standpoint. Many miRNA clusters coordinately regulate multiple members of cellular signaling pathways or protein interaction networks. This cooperative method of targeting could produce effects on an overall process that are much more dramatic than the smaller effects often associated with regulation by an individual miRNA. In this study, we screened 366 human miRNA minigenes to determine their effects on the major signaling pathways culminating in AP-1, NF-κB, c-Myc, or p53 transcriptional activity. By stratifying these data into miRNA clusters, this systematic screen provides experimental evidence for the combined effects of clustered miRNAs on these signaling pathways. We also verify p53 as a direct target of miR-200a. This study is the first to provide a panoramic view of miRNA clusters' effects on cellular pathways.

Single nucleotide variation in the TP53 3′ untranslated region in diffuse large B-cell lymphoma treated with rituximab-CHOP: a report from the International DLBCL Rituximab-CHOP Consortium Program

“…Eleven miRNAs are reported to target the human TP53 gene: miR-25, miR-30d, 20 miR-125b, 21 miR-504, 22 miR-380-5p, 23 miR-92a, miR-141, 24 miR-200a, 25 miR-1285, 26 miR-15a, and miR-16. 27 Among these miRNAs, 3 pairs have the same seed sequence: miR-25 and miR92a, miR-141 and miR-200a, and miR-15a and miR-16.…”

Developing microRNA screening as a functional genomics tool for disease research

“…The study first used an in silico approach comparing miRNA target sites from published PAR-CLIP dataset (Hafner et al, 2010) to proteomics datasets (Baek et al, 2008; Selbach et al, 2008) to conclude that miRNAs have a propensity to target proteins involved in multi-protein complexes. Furthermore, they showed that protein complexes are coordinately regulated by clusters of miRNAs, a conclusion supported by an analysis of miRNAs that regulate transcription factor response elements in cell culture (Becker et al, 2012). To probe the notion that miRNA clusters coordinately control biological processes, Sass et al (2011) went on to show that additional members of the transcriptional complex controlling E-cadherin, in addition to previously identified members, are under coordinate control by miRNAs that reside within the miR141-200c cluster.…”

“…A recent study Becker et al (2012) shows that miRs are encoded in the genome as individual miRNA genes or as gene clusters and transcribed as polycistronic units. These authors estimated that about 50% of all miRNAs are co-expressed with neighboring miRNAs and, most importantly, that these clusters coordinately regulate multiple members of protein-protein interaction network clusters.…”

“…These authors estimated that about 50% of all miRNAs are co-expressed with neighboring miRNAs and, most importantly, that these clusters coordinately regulate multiple members of protein-protein interaction network clusters. Another study (Alshalalfa et al, 2012) showed that combining protein functional interaction networks with miR detection revealed several miR-regulated interaction modules that were indeed enriched in focal adhesion and prostate cancer pathways, and yet another used screen data to reveal miRNA control of p53 (Becker et al, 2012). Illustrative of such recent efforts to deduce high quality PPIs from miRNA screen datasets is the control of epithelial to mesenchymal transition by miR-200 family (Sass et al, 2011).…”

Augmentation of Ras-induced cell transformation : a new role for miR-200a in malignancy.

“…This DSB-detection signal recruits p53, which is then phosphorylated on its N-terminus at serine 15 by DNA-PK or ATM. Phosphorylation at this site blocks inhibition by Mdm2 and promotes binding to p53 response elements in the promoter regions of proapoptotic genes [41,52,53].…”