The Translational Landscape of the Human Heart

• Published in: Cell Vol. 178; no. 1; pp. 242 - 260.e29
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27-06-2019
• Subjects: Adolescent; Adult; Aged; Animals; circRNAs; Codon - genetics; dilated cardiomyopathy; Female; Gene Expression Regulation; heart failure; HEK293 Cells; human heart; Humans; Infant; lncRNAs; Male; Mice; Mice, Inbred C57BL; microproteins; Middle Aged; Myocardium - metabolism; Open Reading Frames - genetics; ORF detection; Protein Biosynthesis; protein-truncating variants; Rats; ribosome profiling; Ribosomes - genetics; Ribosomes - metabolism; RNA, Circular - genetics; RNA, Circular - metabolism; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; short ORFs; titin; translational regulation; translatome; Young Adult; lncRNAs; heart failure; circRNAs; microproteins; titin; ribosome profiling; human heart; protein-truncating variants; short ORFs; translatome; translational regulation; ORF detection; dilated cardiomyopathy
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2019.05.010

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 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.
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•Ribosome profiling reveals the principles of translational control in human tissue•Ribosomes translate mRNAs downstream of protein-truncating variants•Functionally characterized lncRNAs and circRNAs produce microproteins in vivo•Microproteins can be implicated in mitochondrial and other cellular processes
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.