Control of Gene Expression by RNA Binding Protein Action on Alternative Translation Initiation Sites.

Angela Re,Levi Waldron,Alessandro Quattrone

doi:10.1371/journal.pcbi.1005198

Angela Re, Levi Waldron + Show 1 more

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https://doi.org/10.1371/journal.pcbi.1005198

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Abstract

Transcript levels do not faithfully predict protein levels, due to post-transcriptional regulation of gene expression mediated by RNA binding proteins (RBPs) and non-coding RNAs. We developed a multivariate linear regression model integrating RBP levels and predicted RBP-mRNA regulatory interactions from matched transcript and protein datasets. RBPs significantly improved the accuracy in predicting protein abundance of a portion of the total modeled mRNAs in three panels of tissues and cells and for different methods employed in the detection of mRNA and protein. The presence of upstream translation initiation sites (uTISs) at the mRNA 5’ untranslated regions was strongly associated with improvement in predictive accuracy. On the basis of these observations, we propose that the recently discovered widespread uTISs in the human genome can be a previously unappreciated substrate of translational control mediated by RBPs.

Highlights

High throughput technologies such as RNA-sequencing (RNA-seq) and mass-spectrometrybased protein analyses provide transcriptomic and proteomic profiles, which are the basis to draft a comprehensive picture of gene expression regulation [1],[2],[3].Several studies have reported a lack of concordance between transcriptome and the proteome profiles [3],[4],[5],[6],[7], both at the steady state [8],[9],[10] and dynamically [11],[12], [13]
The results of our analyses restricted the utility of RNA binding proteins (RBPs) to improve accuracy of predicted protein abundance to a small fraction of the total modelled genes, and identified a novel association of the improvement induced by RBPs with the presence of upstream translation sites
This finding suggests a new avenue of experimental studies aimed at exploring the hypothesis that RBPs could influence protein abundance by changing the preference for certain translation initiation sites

Summary

Introduction

Several studies have reported a lack of concordance between transcriptome and the proteome profiles [3],[4],[5],[6],[7], both at the steady state [8],[9],[10] and dynamically [11],[12], [13]. Even though this phenomenon is partially accounted for by technical factors such as noise [14], biased detection [15] and limited and variable coverage of mRNA and protein measurements [16], the discrepancy is so considerable that undoubtedly it implies an unresolved complexity in the regulation of gene expression downstream of transcription. Employing additional statistical efforts to account for the influence of measurement error on mRNA/protein correlation, recent studies proposed a correction of the initial estimates and brought back the role of translation to 30% [18]. Several studies highlighted the strong influence of translation on differential protein abundance during dynamic responses [19], [20], [21], [22]

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