Paper of the Month

June 2019

The Translational Landscape of the Human Heart. Cell. DZHK authors: van Heesch, Schulz, Faber, Mücke, Diecke, Knosalla, Linke, Rajewsky, Hübner

Translational regulation, the process of mRNA translation into proteins by ribosomes, is a crucial component of gene expression regulation. Yet, the act of protein synthesis had not been comprehensively studied in human tissues such as the heart. A team of international scientists led by Dr. Sebastiaan van Heesch and Professor Dr. Norbert Hübner at the MDC Berlin has now investigated mRNA translation across 80 healthy and diseased human hearts, identifying multiple novel aspects of biology and discovering hundreds of previously unknown small proteins.

Using a relatively new technique called ribosome profiling in human tissue samples for the first time, the movement of ribosomes along specific mRNA fragments could be witnessed in human hearts. This highlighted extensive translational control of disease processes such as cardiac fibrosis, and, surprisingly, showed that multiple predicted disease-causing protein truncating variants did not terminate translation efficiently. This included variants in the large sarcomere protein titin, shedding light on the mechanistic consequences of truncating DNA mutations, and how these should be interpreted. This is important because for instance titin-truncating mutations are frequent in the general population, though not all carriers develop heart disease.
Searching for new RNA molecules that ribosomes use as templates for protein production, the authors discovered that the human heart holds even more secrets. Hundreds of long noncoding RNAs and circular RNAs produced previously undetected microproteins, which mostly appeared to be involved in cardiac mitochondrial energy metabolism. These tiny proteins may act as modulators of larger complexes or pathways and for several examples, interaction partners could indeed be identified. Importantly, some of the noncoding RNAs that produce microproteins had previously been identified as noncoding modulators of cardiac disease (e.g. myheart, chaer, upperhand, ZFAS1 and TRDN-AS), warranting future investigation into the potential dual coding and noncoding cardiac roles these genes may fulfill.


MDC Press release: Unknown mini-proteins in the heart