Slight Differences – New Insights into the Regulation of Disease-Associated Genes

When a gene is read, its blueprint for proteins encoded in the language of DNA is transcribed in the cell nucleus into RNA. “At this level, many but by far not all of the individual differences in gene regulation can be identified,” said Professor Norbert Hübner, senior author of the publication and head of the research group Genetics and Genomics of Cardiovascular Diseases at the MDC.

Together with Sebastian Schafer (MDC, NHRIS) and Eleonora Adami (MDC) as well as researchers from several research institutions in Berlin, the Netherlands, England and the Czech Republic, they investigated gene regulation on the next level, translation. It takes place outside the cell nucleus, in the cell plasma. During translation, the RNA sequence is translated into amino acid sequences and assembled into proteins in the protein factories of the cell, the ribosomes.

First, the researchers searched the entire genome of two strains of rats, – one strain had high blood pressure, the other strain not – and specifically investigated genes of the heart and liver tissue. Then they used a new technique called ribosome profiling, abbreviated ribo-seq, which enables them to determine what proportion of the transcriptome is actively translated into proteins.

The result: They observed almost double the number of differentially expressed heart and liver genes in translation as in transcription. Next, they compared these data with the corresponding human genes in genome-wide association studies.

This comparison revealed that a large number of heart and liver genes in humans are regulated primarily during translation. The researchers are confident that capturing interindividual differences in the translated genome will lead to new insights into the genes and regulatory pathways underlying disease.

*Translational regulation shapes the molecular landscape of complex disease phenotypes
Sebastian Schafer1,2,*, Eleonora Adami1,*, Matthias Heinig1,3, Katharina E. Costa Rodrigues1, Franziska Kreuchwig1, Jan Silhavy4, Sebastiaan van Heesch1, Deimante Simaite1, Nikolaus Rajewsky5,6, Edwin Cuppen7, Michal Pravenec4, Martin Vingron3, Stuart A. Cook2,8,9 & Norbert Hübner1,6,10
1Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Association, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
2National Heart Research Institute Singapore (NHRIS), National Heart Centre Singapore, Singapore 169609, Singapore.
3Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany.
4Institute of Physiology, Academy of Sciences of the Czech Republic, Vídenska 1083, 142 20 Prague 4, Czech Republic.
5Systems Biology of Gene Regulatory Elements, Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Association, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
6DZHK (German Centre for Cardiovascular Research), Partner Site, 13347 Berlin, Germany.
7Hubrecht Institute-KNAW & University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
8National Heart and Lung Institute, Imperial College London, London SW3 6NP, UK.
9Duke-National University of Singapore, Singapore 169857, Singapore.
10Charité Universitätsmedizin, 10117 Berlin, Germany.
* These authors contributed equally to this work.

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