Trans control of cardiac mRNA translation in a protein length-dependent fashion [article]

Franziska Witte, Jorge Ruiz-Orera, Camilla Ciolli Mattioli, Susanne Blachut, Eleonora Adami, Jana Felicitas Schulz, Valentin Schneider-Lunitz, Oliver Hummel, Giannino Patone, Michael Benedikt Mucke, Jan Silhavy, Matthias Heinig (+7 others)
2020 biorxiv/medrxiv   pre-print
Little is known about the impact of naturally occurring genetic variation on the rates with which proteins are synthesized by ribosomes. Here, we investigate how genetic influences on mRNA translational efficiency are associated with complex disease phenotypes using a panel of rat recombinant inbred lines. We identify a locus for cardiac hypertrophy that is associated with a translatome-wide and protein length-dependent shift in translational efficiency. This master regulator primarily affects
more » ... he translation of very short and very long protein-coding sequences, altering the physiological stoichiometric translation rates of sarcomere proteins. Mechanistic dissection of this locus points to altered ribosome assembly, characterized by accumulation of polysome half-mers, changed ribosomal configurations and misregulation of the small nucleolar RNA SNORA48. We postulate that this locus enhances a pre-existing negative correlation between protein length and translation initiation in diseased hearts. Our work shows that a single genomic locus can trigger a complex, translation-driven molecular mechanism that contributes to phenotypic variability between individuals.
doi:10.1101/2020.06.05.133298 fatcat:mbjtrxcgivadhocyw4w3dtn4qu