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Nucleic Acids Res. 2016 May 19;44(9):e83. doi: 10.1093/nar/gkw048. Epub 2016 Feb 2.

Modeling the combined effect of RNA-binding proteins and microRNAs in post-transcriptional regulation.

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Graduate School of Informatics, Department of Health Informatics, Middle East Technical University, Üniversiteler Mahallesi, Dumlupınar Bulvarı, No:1, 06800 Ankara, Turkey.
Einthoven Laboratory of Experimental Vascular Medicine, Albinusdreef 2, 2333 ZA Leiden, The Netherlands Department of Nephrology, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
Department of Computer Engineering, Antalya International University, Çıplaklı Mahallesi, Farabi Caddesi No:23, 07190 Döşemealtı, Antalya, Turkey


Recent studies show that RNA-binding proteins (RBPs) and microRNAs (miRNAs) function in coordination with each other to control post-transcriptional regulation (PTR). Despite this, the majority of research to date has focused on the regulatory effect of individual RBPs or miRNAs. Here, we mapped both RBP and miRNA binding sites on human 3'UTRs and utilized this collection to better understand PTR. We show that the transcripts that lack competition for HuR binding are destabilized more after HuR depletion. We also confirm this finding for PUM1(2) by measuring genome-wide expression changes following the knockdown of PUM1(2) in HEK293 cells. Next, to find potential cooperative interactions, we identified the pairs of factors whose sites co-localize more often than expected by random chance. Upon examining these results for PUM1(2), we found that transcripts where the sites of PUM1(2) and its interacting miRNA form a stem-loop are more stabilized upon PUM1(2) depletion. Finally, using dinucleotide frequency and counts of regulatory sites as features in a regression model, we achieved an AU-ROC of 0.86 in predicting mRNA half-life in BEAS-2B cells. Altogether, our results suggest that future studies of PTR must consider the combined effects of RBPs and miRNAs, as well as their interactions.

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