Translational regulation shapes the molecular landscape of complex disease phenotypes

Sebastian Schafer, Eleonora Adami, Matthias Heinig, Katharina E. Costa Rodrigues, Franziska Kreuchwig, Jan Silhavy, Sebastiaan van Heesch, Deimante Simaite, Nikolaus Rajewsky, Edwin Cuppen, Michal Pravenec, Martin Vingron, Stuart A. Cook and Norbert Hubner ()
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Sebastian Schafer: Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association
Eleonora Adami: Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association
Matthias Heinig: Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association
Katharina E. Costa Rodrigues: Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association
Franziska Kreuchwig: Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association
Jan Silhavy: Institute of Physiology, Academy of Sciences of the Czech Republic, Vídenska 1083, 142 20 Prague 4, Czech Republic
Sebastiaan van Heesch: Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association
Deimante Simaite: Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association
Nikolaus Rajewsky: Systems Biology of Gene Regulatory Elements, Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association
Edwin Cuppen: Hubrecht Institute-KNAW & University Medical Center Utrecht
Michal Pravenec: Institute of Physiology, Academy of Sciences of the Czech Republic, Vídenska 1083, 142 20 Prague 4, Czech Republic
Martin Vingron: Max Planck Institute for Molecular Genetics
Stuart A. Cook: National Heart Research Institute Singapore (NHRIS), National Heart Centre Singapore
Norbert Hubner: Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association

Nature Communications, 2015, vol. 6, issue 1, 1-9

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8200

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