Translational regulation shapes the molecular landscape of complex disease phenotypes.

Sebastian Schafer,Katharina E Costa Rodrigues,Edwin Cuppen,Stuart A Cook,Sebastiaan Van Heesch,Matthias Heinig,Eleonora Adami,Jan Silhavy,Nikolaus Rajewsky,Martin Vingron,Michal Pravenec,Franziska Kreuchwig,Deimante Simaite,Norbert Hubner

doi:10.1038/ncomms8200

Abstract

The extent of translational control of gene expression in mammalian tissues remains largely unknown. Here we perform genome-wide RNA sequencing and ribosome profiling in heart and liver tissues to investigate strain-specific translational regulation in the spontaneously hypertensive rat (SHR/Ola). For the most part, transcriptional variation is equally apparent at the translational level and there is limited evidence of translational buffering. Remarkably, we observe hundreds of strain-specific differences in translation, almost doubling the number of differentially expressed genes. The integration of genetic, transcriptional and translational data sets reveals distinct signatures in 3′UTR variation, RNA-binding protein motifs and miRNA expression associated with translational regulation of gene expression. We show that a large number of genes associated with heart and liver traits in human genome-wide association studies are primarily translationally regulated. Capturing interindividual differences in the translated genome will lead to new insights into the genes and regulatory pathways underlying disease phenotypes.

Highlights

The extent of translational control of gene expression in mammalian tissues remains largely unknown
Several genetic disorders are believed to be caused by mutations that affect protein translation[3], but so far genome-wide translation has not been studied in complex disease models. It remains a matter of debate how well transcript abundances explain protein levels[4,5], to what extent RNA expression differences are mirrored by the proteome[6,7,8,9,10] and how many genes are under translational control in mammalian tissues
To distinguish translational from transcriptional regulation of gene expression, we integrated two distinct RNA-seq experiments: one polyA-selected data set (RNA-seq1) and one ribosomal RNA-depleted data set (RNA-seq2), which was generated in parallel to ribosome

Summary

Introduction

The extent of translational control of gene expression in mammalian tissues remains largely unknown. We perform genome-wide RNA sequencing and ribosome profiling in heart and liver tissues to investigate strain-specific translational regulation in the spontaneously hypertensive rat (SHR/Ola). Several genetic disorders are believed to be caused by mutations that affect protein translation[3], but so far genome-wide translation has not been studied in complex disease models It remains a matter of debate how well transcript abundances explain protein levels[4,5], to what extent RNA expression differences are mirrored by the proteome[6,7,8,9,10] and how many genes are under translational control in mammalian tissues. The integration of transcriptional and post-transcriptional control of gene expression identifies distinct molecular signatures and reveals the contribution of genetic variation, microRNAs (miRNAs) and RNA-binding proteins (RBPs) to translational regulation. Many genes associated with cardiac and hepatic traits in humans are translationally, and not transcriptionally, regulated in disease tissue

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