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A trans locus causes a ribosomopathy in hypertrophic hearts that affects mRNA translation in a protein length-dependent fashion
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SYSNO ASEP 0543910 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název A trans locus causes a ribosomopathy in hypertrophic hearts that affects mRNA translation in a protein length-dependent fashion Tvůrce(i) Witte, F. (DE)
Ruiz-Orera, J. (DE)
Mattioli, C. C. (DE)
Blachut, S. (DE)
Adami, E. (DE)
Schulz, J. F. (DE)
Schneider-Lunitz, V. (DE)
Hummel, O. (DE)
Patone, G. (DE)
Mücke, M. B. (DE)
Šilhavý, Jan (FGU-C) RID, ORCID
Heinig, M. (DE)
Bottolo, L. (GB)
Sanchis, D. (ES)
Vingron, M. (DE)
Chekulaeva, M. (DE)
Pravenec, Michal (FGU-C) RID, ORCID
Hubner, N. (DE)
van Heesch, S. (DE)Číslo článku 191 Zdroj.dok. Genome Biology - ISSN 1474-760X
Roč. 22, č. 1 (2021)Poč.str. 34 s. Jazyk dok. eng - angličtina Země vyd. GB - Velká Británie Klíč. slova genetic variation ; trans QTL mapping ; translational efficiency ; ribosome profiling ; cardiac hypertrophy ; spontaneously hypertensive rats (SHR) Vědní obor RIV FA - Kardiovaskulární nemoci vč. kardiochirurgie Obor OECD Cardiac and Cardiovascular systems Způsob publikování Open access Institucionální podpora FGU-C - RVO:67985823 UT WOS 000669599400002 EID SCOPUS 85109219819 DOI 10.1186/s13059-021-02397-w Anotace Background Little is known about the impact of trans-acting genetic variation on the rates with which proteins are synthesized by ribosomes. Here, we investigate the influence of such distant genetic loci on the efficiency of mRNA translation and define their contribution to the development of complex disease phenotypes within a panel of rat recombinant inbred lines. Results We identify several tissue-specific master regulatory hotspots that each control the translation rates of multiple proteins. One of these loci is restricted to hypertrophic hearts, where it drives a translatome-wide and protein length-dependent change in translational efficiency, altering the stoichiometric translation rates of sarcomere proteins. Mechanistic dissection of this locus across multiple congenic lines points to a translation machinery defect, characterized by marked differences in polysome profiles and misregulation of the small nucleolar RNA SNORA48. Strikingly, from yeast to humans, we observe reproducible protein length-dependent shifts in translational efficiency as a conserved hallmark of translation machinery mutants, including those that cause ribosomopathies. Depending on the factor mutated, a pre-existing negative correlation between protein length and translation rates could either be enhanced or reduced, which we propose to result from mRNA-specific imbalances in canonical translation initiation and reinitiation rates. Conclusions We show that distant genetic control of mRNA translation is abundant in mammalian tissues, exemplified by a single genomic locus that triggers a translation-driven molecular mechanism. Our work illustrates the complexity through which genetic variation can drive phenotypic variability between individuals and thereby contribute to complex disease. Pracoviště Fyziologický ústav Kontakt Lucie Trajhanová, lucie.trajhanova@fgu.cas.cz, Tel.: 241 062 400 Rok sběru 2022 Elektronická adresa https://doi.org/10.1186/s13059-021-02397-w
Počet záznamů: 1