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Cell. 2019 May 29. pii: S0092-8674(19)30508-2. doi: 10.1016/j.cell.2019.05.010. [Epub ahead of print]

The Translational Landscape of the Human Heart.

Author information

1
Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany. Electronic address: sebastiaanvanheesch@gmail.com.
2
Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany.
3
Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany; Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore, Singapore 169857, Singapore.
4
Proteomics Platform, Berlin Institute of Health (BIH) and Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany.
5
Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore, Singapore 169857, Singapore; National Heart Research Institute Singapore (NHRIS), National Heart Centre Singapore, Singapore 169609, Singapore.
6
Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 10115 Berlin, Germany; Department of Biology, Humboldt Universität Berlin, 10099 Berlin, Germany.
7
Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 10115 Berlin, Germany.
8
Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 10115 Berlin, Germany; Core Unit Bioinformatics, Berlin Institute of Health (BIH), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and Charité-Universitätsmedizin, 10117 Berlin, Germany.
9
Cardiovascular Research Centre, Royal Brompton and Harefield NHS Trust, SW3 6NP London, UK; National Heart and Lung Institute, Imperial College London, SW3 6LY London, UK.
10
Cardiovascular Research Centre, Royal Brompton and Harefield NHS Trust, SW3 6NP London, UK; National Heart and Lung Institute, Imperial College London, SW3 6LY London, UK; MRC-London Institute of Medical Sciences, Hammersmith Hospital Campus, London W12 0NN, UK.
11
National Heart and Lung Institute, Imperial College London, SW3 6LY London, UK; MRC-London Institute of Medical Sciences, Hammersmith Hospital Campus, London W12 0NN, UK.
12
Pluripotent Stem Cells Platform, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 13347 Berlin, Germany; Berlin Institute of Health (BIH), 10178 Berlin, Germany.
13
Department of Rheumatology and Clinical Immunology, Sapporo City General Hospital, Sapporo, Hokkaido 060-8604, Japan.
14
Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany.
15
Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; First Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
16
First Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
17
Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, the Netherlands; Department of Pathology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, the Netherlands.
18
Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, the Netherlands; Durrer Center for Cardiovascular Research, Netherlands Heart Institute, 3511 EP Utrecht, Utrecht, the Netherlands; Farr Institute of Health Informatics Research and Institute of Health Informatics, University College London, NW1 2DA London, UK.
19
Department of Pathology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, the Netherlands.
20
Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore, Singapore 169857, Singapore.
21
Herz- und Diabeteszentrum NRW, Universitätsklinikum der Ruhr-Universität, Erich und Hanna Klessmann-Institut für Kardiovaskuläre Forschung und Entwicklung, 32545 Bad Oeynhausen, Germany.
22
Discipline of Anatomy and Histology, Bosch Institute, Anderson Stuart Building, University of Sydney, Sydney, NSW 2006, Australia.
23
DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 13347 Berlin, Germany; Department of Cardiothoracic and Vascular Surgery, German Heart Center Berlin, 13353 Berlin, Germany; Charité-Universitätsmedizin, 10117 Berlin, Germany.
24
Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 10115 Berlin, Germany; IRI Life Sciences, Institute für Biologie, Humboldt Universität zu Berlin, 10115 Berlin, Germany.
25
Max Planck Institute for Molecular Genetics, Department of Computational Molecular Biology, 14195 Berlin, Germany.
26
Institute of Physiology II, University of Münster, 48149 Münster, Germany; DZHK (German Center for Cardiovascular Research), Partner Site Göttingen, 37075 Göttingen, Germany.
27
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
28
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
29
Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore, Singapore 169857, Singapore; National Heart Research Institute Singapore (NHRIS), National Heart Centre Singapore, Singapore 169609, Singapore; National Heart and Lung Institute, Imperial College London, SW3 6LY London, UK; MRC-London Institute of Medical Sciences, Hammersmith Hospital Campus, London W12 0NN, UK.
30
Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 13347 Berlin, Germany; Berlin Institute of Health (BIH), 10178 Berlin, Germany; Charité-Universitätsmedizin, 10117 Berlin, Germany. Electronic address: nhuebner@mdc-berlin.de.

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 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.

KEYWORDS:

ORF detection; circRNAs; dilated cardiomyopathy; heart failure; human heart; lncRNAs; microproteins; protein-truncating variants; ribosome profiling; short ORFs; titin; translational regulation; translatome

PMID:
31155234
DOI:
10.1016/j.cell.2019.05.010

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