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.

• MeSH
• biogeneze organel MeSH
• genetická variace MeSH
• iniciace translace peptidového řetězce * MeSH
• kardiomegalie genetika   metabolismus   patologie   MeSH
• krysa rodu rattus MeSH
• lokus kvantitativního znaku * MeSH
• malá jadérková RNA genetika   metabolismus   MeSH
• messenger RNA genetika   metabolismus   MeSH
• myokard metabolismus   patologie   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• potkani inbrední SHR MeSH
• potkani transgenní MeSH
• regulace genové exprese MeSH
• ribozomální proteiny genetika   metabolismus   MeSH
• ribozomy genetika   metabolismus   patologie   MeSH
• Saccharomyces cerevisiae genetika   metabolismus   MeSH
• sarkomery metabolismus   patologie   MeSH
• stanovení celkové genové exprese MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

• Publikační typ
• tisková chyba MeSH

Cardiac fibrosis is a final common pathology in inherited and acquired heart diseases that causes cardiac electrical and pump failure. Here, we use systems genetics to identify a pro-fibrotic gene network in the diseased heart and show that this network is regulated by the E3 ubiquitin ligase WWP2, specifically by the WWP2-N terminal isoform. Importantly, the WWP2-regulated pro-fibrotic gene network is conserved across different cardiac diseases characterized by fibrosis: human and murine dilated cardiomyopathy and repaired tetralogy of Fallot. Transgenic mice lacking the N-terminal region of the WWP2 protein show improved cardiac function and reduced myocardial fibrosis in response to pressure overload or myocardial infarction. In primary cardiac fibroblasts, WWP2 positively regulates the expression of pro-fibrotic markers and extracellular matrix genes. TGFβ1 stimulation promotes nuclear translocation of the WWP2 isoforms containing the N-terminal region and their interaction with SMAD2. WWP2 mediates the TGFβ1-induced nucleocytoplasmic shuttling and transcriptional activity of SMAD2.

• MeSH
• dospělí MeSH
• extracelulární matrix - proteiny metabolismus   MeSH
• fibróza genetika   metabolismus   MeSH
• genetická predispozice k nemoci * genetika   MeSH
• genové regulační sítě * MeSH
• kardiomyopatie genetika   metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• myši transgenní MeSH
• myši MeSH
• nemoci srdce genetika   metabolismus   MeSH
• protein - isoformy MeSH
• protein Smad2 genetika   metabolismus   MeSH
• regulace genové exprese MeSH
• senioři MeSH
• transformující růstový faktor beta metabolismus   MeSH
• ubikvitinligasy genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• myši MeSH
• senioři MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Coronary flow (CF) measured ex vivo is largely determined by capillary density that reflects angiogenic vessel formation in the heart in vivo. Here we exploit this relationship and show that CF in the rat is influenced by a locus on rat chromosome 2 that is also associated with cardiac capillary density. Mitochondrial tryptophanyl-tRNA synthetase (Wars2), encoding an L53F protein variant within the ATP-binding motif, is prioritized as the candidate at the locus by integrating genomic data sets. WARS2(L53F) has low enzyme activity and inhibition of WARS2 in endothelial cells reduces angiogenesis. In the zebrafish, inhibition of wars2 results in trunk vessel deficiencies, disordered endocardial-myocardial contact and impaired heart function. Inhibition of Wars2 in the rat causes cardiac angiogenesis defects and diminished cardiac capillary density. Our data demonstrate a pro-angiogenic function for Wars2 both within and outside the heart that may have translational relevance given the association of WARS2 with common human diseases.

• MeSH
• dánio pruhované MeSH
• embryo nesavčí MeSH
• endoteliální buňky pupečníkové žíly (lidské) cytologie   enzymologie   MeSH
• fyziologická neovaskularizace genetika   MeSH
• genetické lokusy MeSH
• genom * MeSH
• HEK293 buňky MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• malá interferující RNA genetika   metabolismus   MeSH
• mapování chromozomů MeSH
• mitochondrie genetika   metabolismus   MeSH
• myokard cytologie   enzymologie   MeSH
• savčí chromozomy chemie   MeSH
• sekvence aminokyselin MeSH
• sekvenční homologie aminokyselin MeSH
• sekvenční seřazení MeSH
• signální transdukce MeSH
• tryptofan-tRNA-ligasa antagonisté a inhibitory   genetika   metabolismus   MeSH
• vývojová regulace genové exprese * MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH