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, Norbert Hubner

Research output: Contribution to journalArticlepeer-review

48 Citations (Scopus)

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.

Original languageEnglish
Article number7200
Pages (from-to)7200
JournalNature communications
Volume6
DOIs
Publication statusPublished - 26 May 2015
Externally publishedYes

Keywords

  • Animals
  • Gene Expression Regulation
  • Hypertension/metabolism
  • Liver/metabolism
  • Male
  • Myocardium/metabolism
  • Phenotype
  • Proteome
  • Rats, Inbred BN
  • Rats, Inbred SHR
  • Ribosomes/metabolism
  • Sequence Analysis, RNA

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