The Translational Landscape of the Human Heart
van Heesch, Sebastiaan; Witte, Franziska; Schneider-Lunitz, Valentin; Schulz, Jana F; Adami, Eleonora; Faber, Allison B; Kirchner, Marieluise; Maatz, Henrike; Blachut, Susanne; Sandmann, Clara-Louisa; Kanda, Masatoshi; Worth, Catherine L; Schafer, Sebastian; Calviello, Lorenzo; Merriott, Rhys; Patone, Giannino; Hummel, Oliver; Wyler, Emanuel; Obermayer, Benedikt; Mücke, Michael B; Lindberg, Eric L; Trnka, Franziska; Memczak, Sebastian; Schilling, Marcel; Felkin, Leanne E; Barton, Paul J R; Quaife, Nicholas M; Vanezis, Konstantinos; Diecke, Sebastian; Mukai, Masaya; Mah, Nancy; Oh, Su-Jun; Kurtz, Andreas; Schramm, Christoph; Schwinge, Dorothee; Sebode, Marcial; Harakalova, Magdalena; Asselbergs, Folkert W; Vink, Aryan; de Weger, Roel A; Viswanathan, Sivakumar; Widjaja, Anissa A; Gärtner-Rommel, Anna; Milting, Hendrik; Dos Remedios, Cris; Knosalla, Christoph; Mertins, Philipp; Landthaler, Markus; Vingron, Martin; Linke, Wolfgang A; Seidman, Jonathan G; Seidman, Christine E; Rajewsky, Nikolaus; Ohler, Uwe; Cook, Stuart A; Hubner, Norbert
(2019) Cell, volume 178, issue 1, pp. 242 - 260.e29
(Article)
Abstract
Gene expression in human tissue has primarily been studied on the transcriptional level, largely neglecting translational regulation. Here, we analyze the translatomes of 80 human hearts to identify new translation events and quantify the effect of translational regulation. We show extensive translational control of cardiac gene expression, which is orchestrated
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in a process-specific manner. Translation downstream of predicted disease-causing protein-truncating variants appears to be frequent, suggesting inefficient translation termination. We identify hundreds of previously undetected microproteins, expressed from lncRNAs and circRNAs, for which we validate the protein products in vivo. The translation of microproteins is not restricted to the heart and prominent in the translatomes of human kidney and liver. We associate these microproteins with diverse cellular processes and compartments and find that many locate to the mitochondria. Importantly, dozens of microproteins are translated from lncRNAs with well-characterized noncoding functions, indicating previously unrecognized biology. Translational profiling in a primary human tissue reveals frequent translation downstream of predicted disease-causing variants as well as translation of hundreds of microproteins from long noncoding RNAs and circular RNAs.
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Keywords: circRNAs, dilated cardiomyopathy, heart failure, human heart, lncRNAs, microproteins, ORF detection, protein-truncating variants, ribosome profiling, short ORFs, titin, translational regulation, translatome, General Biochemistry,Genetics and Molecular Biology, Journal Article
ISSN: 0092-8674
Publisher: Cell Press
Note: Funding Information: S.v.H. was supported by an EMBO long-term fellowship ( ALTF 186-2015 , LTFCOFUND2013 , GA-2013-609409 ). N.H. is the recipient of an ERC advanced grant under the European Union Horizon 2020 Research and Innovation Program (grant agreement AdG788970 ). C.E.S., J.G.S., S.A.C., and N.H. are supported by a grant from the Leducq Foundation ( 16CVD03 ). N.H., M.L. and U.O. were supported by the Federal Ministry of Education and Research of Germany in the framework of CaRNAtion ( 031L0075A ). W.A.L. was supported by the German Research Foundation ( SFB1002 and TPA08 ). S.A.C., P.J.R.B., and L.E.F. received support from the British Heart Foundation , the Medical Research Council (UK), the NIHR Imperial College Biomedical Research Centre , the NIHR Cardiovascular BRU of Royal Brompton & Harefield NHS Foundation Trust UK , the Imperial College Academic Health Science Centre , and Heart Research UK . N.M.Q. is funded by the Imperial College Academic Health Science Centre . M. Kanda received funding provided by the Alexander von Humboldt Foundation . L.C. and U.O. were supported by the German Federal Ministry of Education and Research in the framework of RNA Bioinformatics Center of the German Network for Bioinformatics Infrastructure (de.NBI; BMBF 031 A538C ). Funding Information: S.v.H. was supported by an EMBO long-term fellowship (ALTF 186-2015, LTFCOFUND2013, GA-2013-609409). N.H. is the recipient of an ERC advanced grant under the European Union Horizon 2020 Research and Innovation Program (grant agreement AdG788970). C.E.S. J.G.S. S.A.C. and N.H. are supported by a grant from the Leducq Foundation (16CVD03). N.H. M.L. and U.O. were supported by the Federal Ministry of Education and Research of Germany in the framework of CaRNAtion (031L0075A). W.A.L. was supported by the German Research Foundation (SFB1002 and TPA08). S.A.C. P.J.R.B. and L.E.F. received support from the British Heart Foundation, the Medical Research Council (UK), the NIHR Imperial College Biomedical Research Centre, the NIHR Cardiovascular BRU of Royal Brompton & Harefield NHS Foundation Trust UK, the Imperial College Academic Health Science Centre, and Heart Research UK. N.M.Q. is funded by the Imperial College Academic Health Science Centre. M. Kanda received funding provided by the Alexander von Humboldt Foundation. L.C. and U.O. were supported by the German Federal Ministry of Education and Research in the framework of RNA Bioinformatics Center of the German Network for Bioinformatics Infrastructure (de.NBI; BMBF 031 A538C). Conceptualization, S.v.H. and N.H.; Methodology, S.v.H. F.W. V.S.-L. J.F.S. E.A. L.C. U.O. and N.H.; Software, F.W. V.S.-L. A.B.F. C.L.W. B.O. M. Schilling, L.C. and U.O.; Validation, J.F.S. C.-L.S. S.B. S.v.H. E.W. R.M. M. Kirchner, S.M. E.L.-H.L. F.T. and P.M.; Formal Analysis, F.W. V.S.-L. A.B.F. C.L.W. G.P. M.V. and O.H.; Investigation, S.v.H. J.F.S. E.A. S.B. M. Kirchner, M. Kanda, N.M.Q. K.V. M.B.M. Y.K. M.L. N.R. F.W. and V.S.-L.; Resources, M.H. F.W.A. A.V. R.A.d.W. C.K. W.A.L. C.d.R. H. Milting, A.G.-R. P.J.R.B. L.E.F. J.G.S. C.E.S. M. Kanda, M.M. N.M. S.-J.O. A.K. M. Sebode, C.S. D.S. S.D. S.S. S.V. A.A.W. and S.A.C.; Data Curation, F.W. V.S.-L. C.L.W. A.B.F. and S.v.H.; Writing – Original Draft, S.v.H.; Writing – Review & Editing, S.v.H. H. Maatz, C.-L.S. J.F.S. F.W. V.S.-L. A.B.F. C.L.W. S.A.C. and N.H. with input from all authors; Visualization, S.v.H. F.W. V.S.-L. A.B.F. J.F.S. C.L.W. and E.A.; Supervision, S.v.H. and N.H.; Project Administration, S.v.H. and N.H.; Funding Acquisition, S.v.H. and N.H. The authors declare no competing interests. Publisher Copyright: © 2019 Elsevier Inc.
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