Počet záznamů: 1  

A trans locus causes a ribosomopathy in hypertrophic hearts that affects mRNA translation in a protein length-dependent fashion

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    SYSNO ASEP0543910
    Druh ASEPJ - Článek v odborném periodiku
    Zařazení RIVJ - Článek v odborném periodiku
    Poddruh JČlánek ve WOS
    NázevA 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 článku191
    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. slovagenetic variation ; trans QTL mapping ; translational efficiency ; ribosome profiling ; cardiac hypertrophy ; spontaneously hypertensive rats (SHR)
    Vědní obor RIVFA - Kardiovaskulární nemoci vč. kardiochirurgie
    Obor OECDCardiac and Cardiovascular systems
    Způsob publikováníOpen access
    Institucionální podporaFGU-C - RVO:67985823
    UT WOS000669599400002
    EID SCOPUS85109219819
    AnotaceBackground 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.
    PracovištěFyziologický ústav
    KontaktLucie Trajhanová, lucie.trajhanova@fgu.cas.cz, Tel.: 241 062 400
    Rok sběru2022
    Elektronická adresahttps://doi.org/10.1186/s13059-021-02397-w
Počet záznamů: 1