Pathogenic variants damage cell composition and single cell transcription in cardiomyopathies-Reference-Cited by-同舟云学术

Pathogenic variants damage cell composition and single cell transcription in cardiomyopathies

Published:2022-08-05 Issue:6606 Volume:377 Page:
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Reichart Daniel¹²³^ORCID,Lindberg Eric L.⁴^ORCID,Maatz Henrike⁴⁵^ORCID,Miranda Antonio M. A.⁶⁷,Viveiros Anissa⁸⁹^ORCID,Shvetsov Nikolay⁴^ORCID,Gärtner Anna¹⁰^ORCID,Nadelmann Emily R.¹^ORCID,Lee Michael⁶^ORCID,Kanemaru Kazumasa¹¹^ORCID,Ruiz-Orera Jorge⁴^ORCID,Strohmenger Viktoria¹¹²^ORCID,DeLaughter Daniel M.¹¹³^ORCID,Patone Giannino⁴^ORCID,Zhang Hao⁸⁹,Woehler Andrew¹⁴^ORCID,Lippert Christoph¹⁵¹⁶^ORCID,Kim Yuri¹²^ORCID,Adami Eleonora⁴,Gorham Joshua M.¹^ORCID,Barnett Sam N.⁶,Brown Kemar¹¹⁷^ORCID,Buchan Rachel J.⁶¹⁸^ORCID,Chowdhury Rasheda A.⁶^ORCID,Constantinou Chrystalla⁶,Cranley James¹¹,Felkin Leanne E.⁶¹⁸^ORCID,Fox Henrik¹⁹^ORCID,Ghauri Ahla²⁰^ORCID,Gummert Jan¹⁹^ORCID,Kanda Masatoshi⁴²¹^ORCID,Li Ruoyan¹¹,Mach Lukas⁶¹⁸^ORCID,McDonough Barbara²¹³^ORCID,Samari Sara⁶,Shahriaran Farnoush²²,Yapp Clarence²³^ORCID,Stanasiuk Caroline¹⁰^ORCID,Theotokis Pantazis I.⁶²⁴^ORCID,Theis Fabian J.²²^ORCID,van den Bogaerdt Antoon²⁵,Wakimoto Hiroko¹^ORCID,Ware James S.⁶¹⁸²⁴^ORCID,Worth Catherine L.⁴^ORCID,Barton Paul J. R.⁶¹⁸²⁴^ORCID,Lee Young-Ae²⁰²⁶,Teichmann Sarah A.¹¹²⁷^ORCID,Milting Hendrik¹⁰^ORCID,Noseda Michela⁶⁷^ORCID,Oudit Gavin Y.⁸⁹^ORCID,Heinig Matthias²²²⁸²⁹^ORCID,Seidman Jonathan G.¹^ORCID,Hubner Norbert⁴⁵³⁰^ORCID,Seidman Christine E.¹²¹³^ORCID

Affiliation:

1. Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

2. Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA 02115, USA.

3. Department of Medicine I, University Hospital, LMU Munich, 80336 Munich, Germany.

4. Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany.

5. DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 10785 Berlin, Germany.

6. National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK.

7. British Heart Foundation Centre for Research Excellence and Centre for Regenerative Medicine, Imperial College London, London WC2R 2LS, UK.

8. Division of Cardiology, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2R3, Canada.

9. Mazankowski Alberta Heart Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2R3, Canada.

10. Erich and Hanna Klessmann Institute, Heart and Diabetes Center NRW, University Hospital of the Ruhr-University Bochum, 32545 Bad Oeynhausen, Germany.

11. Cellular Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK.

12. Walter-Brendel-Centre of Experimental Medicine, Ludwig-Maximilian University of Munich, 81377 Munich, Germany.

13. Howard Hughes Medical Institute, Bethesda, MD 20815, USA.

14. Systems Biology Imaging Platform, Berlin Institute for Medical Systems Biology (BIMSB), Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), 10115 Berlin, Germany.

15. Digital Health-Machine Learning group, Hasso Plattner Institute for Digital Engineering, University of Potsdam, 14482 Potsdam, Germany.

16. Hasso Plattner Institute for Digital Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

17. Cardiac Unit, Massachusetts General Hospital, Boston, MA 02114, USA.

18. Royal Brompton and Harefield Hospitals, Guy’s and St. Thomas’ NHS Foundation Trust, London SW3 6NR, UK.

19. Heart and Diabetes Center NRW, Clinic for Thoracic and Cardiovascular Surgery, University Hospital of the Ruhr-University, 32545 Bad Oeynhausen, Germany.

20. Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany.

21. Department of Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan.

22. Computational Health Center, Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), 85764 Neuherberg, Germany.

23. Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA.

24. MRC London Institute of Medical Sciences, Imperial College London, London W12 0NN, UK.

25. ETB-Bislife Foundation, 2300 AH Leiden, Netherlands.

26. Clinic for Pediatric Allergy, Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin, 13125 Berlin, Germany.

27. Department of Physics, Cavendish Laboratory, University of Cambridge, Cambridge CB3 0HE, UK.

28. Department of Informatics, Technische Universitaet Muenchen (TUM), 85748 Munich, Germany.

29. DZHK (German Centre for Cardiovascular Research), Munich Heart Association, Partner Site Munich, 10785 Berlin, Germany.

30. Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.

Abstract

Pathogenic variants in genes that cause dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM) convey high risks for the development of heart failure through unknown mechanisms. Using single-nucleus RNA sequencing, we characterized the transcriptome of 880,000 nuclei from 18 control and 61 failing, nonischemic human hearts with pathogenic variants in DCM and ACM genes or idiopathic disease. We performed genotype-stratified analyses of the ventricular cell lineages and transcriptional states. The resultant DCM and ACM ventricular cell atlas demonstrated distinct right and left ventricular responses, highlighting genotype-associated pathways, intercellular interactions, and differential gene expression at single-cell resolution. Together, these data illuminate both shared and distinct cellular and molecular architectures of human heart failure and suggest candidate therapeutic targets.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Reference128 articles.

1. Dilated Cardiomyopathy

2. Molecular mechanisms of arrhythmogenic cardiomyopathy

3. Epidemiology and risk profile of heart failure

4. Cells of the adult human heart

5. Histone methyltransferase Smyd1 regulates mitochondrial energetics in the heart

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