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

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Item Type:Preprint
Title:Trans control of cardiac mRNA translation in a protein length-dependent fashion
Creators Name:Witte, F. and Ruiz-Orera, J. and Ciolli Mattioli, C. and Blachut, S. and Adami, E. and Schulz, J.F. and Schneider-Lunitz, V. and Hummel, O. and Patone, G. and Mücke, M.B. and Šilhavý, J. and Heinig, M. and Bottolo, L. and Sanchis, D. and Vingron, M. and Chekulaeva, M. and Pravenec, M. and Hubner, N. and van Heesch, S.
Abstract: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 the 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.
Keywords:Genetic Variation, TransQTL Mapping, Translational Efficiency, Ribosome Profiling, Heart, Polysome Profiling, Ribosome Biogenesis, Complex Disease, Spontaneously Hypertensive Rats (SHR), HXB/BXH Rat Recombinant Inbred Panel, Animals, Rats, Mice
Source:bioRxiv
Publisher:Cold Spring Harbor Laboratory Press
Article Number:020.06.05.133298
Date:6 June 2020
Official Publication:https://doi.org/10.1101/2020.06.05.133298

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