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

Saber Hafezqorani,Ruben G De Bruin,Atefeh Lafzi,Eric P Van Der Veer,Yeşim Aydın Son,Anton Jan Van Zonneveld,Hilal Kazan

doi:10.1093/nar/gkw048

Abstract

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.

Highlights

The genetic information of the cell is stored in DNA
For each putative RNAbinding proteins (RBPs) site we keep track of the following information: (i) the start and end position; (ii) a flag showing whether the site is located in a CLIP- or gPARCLIP-determined peak; and (iii) conservation score calculated as the average PhastCons score [49] across the motif (Figure 3.1)
In order to investigate the possible interactions between RBPs and miRNAs, we analyze the co-occurrence of binding sites of all factors with each other

Summary

Introduction

The genetic information of the cell is stored in DNA. Proteins are building blocks that perform all the necessary functions of the cell. The amount of expression of the set of genes is critical and determines the state of a cell. Gene expression has to be regulated precisely. We aim to review the relevant literature about post-transcriptional regulation. We discuss RBPs and their roles as regulators of post-transcriptional gene expression. We cover miRNAs which are key regulators of post-transcriptional gene expression. We continue by introducing various methods for identifying miRNA sites. We discuss RNA secondary structure which plays a crucial role in RBP-target and miRNA-target interactions. We review relevant studies that consider the effect of both RBPs and miRNAs in modeling post-transcriptional gene regulation

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Conclusion