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

F. Witte, J. Ruiz-Orera, CC. Mattioli, S. Blachut, E. Adami, JF. Schulz, V. Schneider-Lunitz, O. Hummel, G. Patone, MB. Mücke, J. Šilhavý, M. Heinig, L. Bottolo, D. Sanchis, M. Vingron, M. Chekulaeva, M. Pravenec, N. Hubner, S. van Heesch

. 2021 ; 22 (1) : 191. [pub] 20210628

Jazyk angličtina Země Velká Británie

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc22012390

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.

Citace poskytuje Crossref.org

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$a A trans locus causes a ribosomopathy in hypertrophic hearts that affects mRNA translation in a protein length-dependent fashion / $c F. Witte, J. Ruiz-Orera, CC. Mattioli, S. Blachut, E. Adami, JF. Schulz, V. Schneider-Lunitz, O. Hummel, G. Patone, MB. Mücke, J. Šilhavý, M. Heinig, L. Bottolo, D. Sanchis, M. Vingron, M. Chekulaeva, M. Pravenec, N. Hubner, S. van Heesch
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$a 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.
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$a Ruiz-Orera, Jorge $u Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125, Berlin, Germany
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$a Mattioli, Camilla Ciolli $u Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 10115, Berlin, Germany $u Present Address: Department of Biological Regulation, Weizmann Institute of Science, 7610001, Rehovot, Israel
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$a Blachut, Susanne $u Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125, Berlin, Germany
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$a Adami, Eleonora $u Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125, Berlin, Germany $u Present Address: Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore, Singapore, 169857, Singapore
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$a Heinig, Matthias $u Institute of Computational Biology (ICB), HMGU, Ingolstaedter Landstr. 1, 85764 Neuherberg, Munich, Germany $u Department of Informatics, Technische Universitaet Muenchen (TUM), Boltzmannstr. 3, 85748 Garching, Munich, Germany
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$a van Heesch, Sebastiaan $u Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125, Berlin, Germany. s.vanheesch@prinsesmaximacentrum.nl $u Present Address: The Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands. s.vanheesch@prinsesmaximacentrum.nl $1 https://orcid.org/0000000195931980
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