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ResearchIn-Press PreviewCardiologyGenetics Open Access | 10.1172/JCI183353

Regulation of sarcomere formation and function in the healthy heart requires a titin intronic enhancer

Yuri Kim,1 Seong Won Kim,2 David Saul,1 Meraj Neyazi,2 Manuel Schmid,2 Hiroko Wakimoto,2 Neil Slaven,3 Joshua H. Lee,4 Olivia G. Layton,2 Lauren K. Wasson,2 Justin H. Letendre,4 Feng Xiao,5 Jourdan K. Ewoldt,4 Konstantinos Gkatzis,6 Peter Sommer,6 Bénédicte Gobert,6 Nicolas Wiest-Daesslé,6 Quentin McAfee,7 Nandita Singhal,1 Mingyue Lun,2 Joshua M. Gorham,2 Zoltan Arany,7 Arun Sharma,8 Christopher N. Toepfer,9 Gavin Y. Oudit,10 William T. Pu,5 Diane E. Dickel,3 Len A. Pennacchio,3 Axel Visel,3 Christopher S. Chen,4 J.G. Seidman,2 and Christine E. Seidman2

1Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Department of Genetics, Harvard Medical School, Boston, United States of America

3Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, United States of America

4Department of Biomedical Engineering, Boston University, Boston, United States of America

5Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, United States of America

6Ksilink, Strasbourg, France

7Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

8Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

9Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

10Department of Medicine, University of Alberta, Edmonton, Canada

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1Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Department of Genetics, Harvard Medical School, Boston, United States of America

3Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, United States of America

4Department of Biomedical Engineering, Boston University, Boston, United States of America

5Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, United States of America

6Ksilink, Strasbourg, France

7Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

8Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

9Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

10Department of Medicine, University of Alberta, Edmonton, Canada

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1Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Department of Genetics, Harvard Medical School, Boston, United States of America

3Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, United States of America

4Department of Biomedical Engineering, Boston University, Boston, United States of America

5Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, United States of America

6Ksilink, Strasbourg, France

7Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

8Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

9Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

10Department of Medicine, University of Alberta, Edmonton, Canada

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1Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Department of Genetics, Harvard Medical School, Boston, United States of America

3Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, United States of America

4Department of Biomedical Engineering, Boston University, Boston, United States of America

5Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, United States of America

6Ksilink, Strasbourg, France

7Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

8Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

9Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

10Department of Medicine, University of Alberta, Edmonton, Canada

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1Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Department of Genetics, Harvard Medical School, Boston, United States of America

3Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, United States of America

4Department of Biomedical Engineering, Boston University, Boston, United States of America

5Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, United States of America

6Ksilink, Strasbourg, France

7Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

8Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

9Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

10Department of Medicine, University of Alberta, Edmonton, Canada

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1Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Department of Genetics, Harvard Medical School, Boston, United States of America

3Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, United States of America

4Department of Biomedical Engineering, Boston University, Boston, United States of America

5Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, United States of America

6Ksilink, Strasbourg, France

7Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

8Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

9Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

10Department of Medicine, University of Alberta, Edmonton, Canada

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1Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Department of Genetics, Harvard Medical School, Boston, United States of America

3Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, United States of America

4Department of Biomedical Engineering, Boston University, Boston, United States of America

5Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, United States of America

6Ksilink, Strasbourg, France

7Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

8Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

9Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

10Department of Medicine, University of Alberta, Edmonton, Canada

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1Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Department of Genetics, Harvard Medical School, Boston, United States of America

3Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, United States of America

4Department of Biomedical Engineering, Boston University, Boston, United States of America

5Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, United States of America

6Ksilink, Strasbourg, France

7Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

8Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

9Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

10Department of Medicine, University of Alberta, Edmonton, Canada

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1Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Department of Genetics, Harvard Medical School, Boston, United States of America

3Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, United States of America

4Department of Biomedical Engineering, Boston University, Boston, United States of America

5Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, United States of America

6Ksilink, Strasbourg, France

7Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

8Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

9Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

10Department of Medicine, University of Alberta, Edmonton, Canada

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1Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Department of Genetics, Harvard Medical School, Boston, United States of America

3Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, United States of America

4Department of Biomedical Engineering, Boston University, Boston, United States of America

5Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, United States of America

6Ksilink, Strasbourg, France

7Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

8Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

9Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

10Department of Medicine, University of Alberta, Edmonton, Canada

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1Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Department of Genetics, Harvard Medical School, Boston, United States of America

3Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, United States of America

4Department of Biomedical Engineering, Boston University, Boston, United States of America

5Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, United States of America

6Ksilink, Strasbourg, France

7Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

8Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

9Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

10Department of Medicine, University of Alberta, Edmonton, Canada

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1Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Department of Genetics, Harvard Medical School, Boston, United States of America

3Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, United States of America

4Department of Biomedical Engineering, Boston University, Boston, United States of America

5Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, United States of America

6Ksilink, Strasbourg, France

7Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

8Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

9Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

10Department of Medicine, University of Alberta, Edmonton, Canada

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1Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Department of Genetics, Harvard Medical School, Boston, United States of America

3Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, United States of America

4Department of Biomedical Engineering, Boston University, Boston, United States of America

5Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, United States of America

6Ksilink, Strasbourg, France

7Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

8Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

9Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

10Department of Medicine, University of Alberta, Edmonton, Canada

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1Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Department of Genetics, Harvard Medical School, Boston, United States of America

3Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, United States of America

4Department of Biomedical Engineering, Boston University, Boston, United States of America

5Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, United States of America

6Ksilink, Strasbourg, France

7Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

8Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

9Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

10Department of Medicine, University of Alberta, Edmonton, Canada

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1Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Department of Genetics, Harvard Medical School, Boston, United States of America

3Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, United States of America

4Department of Biomedical Engineering, Boston University, Boston, United States of America

5Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, United States of America

6Ksilink, Strasbourg, France

7Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

8Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

9Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

10Department of Medicine, University of Alberta, Edmonton, Canada

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1Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Department of Genetics, Harvard Medical School, Boston, United States of America

3Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, United States of America

4Department of Biomedical Engineering, Boston University, Boston, United States of America

5Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, United States of America

6Ksilink, Strasbourg, France

7Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

8Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

9Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

10Department of Medicine, University of Alberta, Edmonton, Canada

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1Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Department of Genetics, Harvard Medical School, Boston, United States of America

3Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, United States of America

4Department of Biomedical Engineering, Boston University, Boston, United States of America

5Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, United States of America

6Ksilink, Strasbourg, France

7Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

8Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

9Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

10Department of Medicine, University of Alberta, Edmonton, Canada

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1Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Department of Genetics, Harvard Medical School, Boston, United States of America

3Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, United States of America

4Department of Biomedical Engineering, Boston University, Boston, United States of America

5Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, United States of America

6Ksilink, Strasbourg, France

7Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

8Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

9Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

10Department of Medicine, University of Alberta, Edmonton, Canada

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1Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Department of Genetics, Harvard Medical School, Boston, United States of America

3Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, United States of America

4Department of Biomedical Engineering, Boston University, Boston, United States of America

5Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, United States of America

6Ksilink, Strasbourg, France

7Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

8Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

9Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

10Department of Medicine, University of Alberta, Edmonton, Canada

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1Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Department of Genetics, Harvard Medical School, Boston, United States of America

3Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, United States of America

4Department of Biomedical Engineering, Boston University, Boston, United States of America

5Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, United States of America

6Ksilink, Strasbourg, France

7Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

8Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

9Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

10Department of Medicine, University of Alberta, Edmonton, Canada

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1Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Department of Genetics, Harvard Medical School, Boston, United States of America

3Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, United States of America

4Department of Biomedical Engineering, Boston University, Boston, United States of America

5Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, United States of America

6Ksilink, Strasbourg, France

7Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

8Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

9Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

10Department of Medicine, University of Alberta, Edmonton, Canada

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1Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Department of Genetics, Harvard Medical School, Boston, United States of America

3Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, United States of America

4Department of Biomedical Engineering, Boston University, Boston, United States of America

5Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, United States of America

6Ksilink, Strasbourg, France

7Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

8Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

9Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

10Department of Medicine, University of Alberta, Edmonton, Canada

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1Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Department of Genetics, Harvard Medical School, Boston, United States of America

3Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, United States of America

4Department of Biomedical Engineering, Boston University, Boston, United States of America

5Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, United States of America

6Ksilink, Strasbourg, France

7Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

8Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

9Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

10Department of Medicine, University of Alberta, Edmonton, Canada

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1Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Department of Genetics, Harvard Medical School, Boston, United States of America

3Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, United States of America

4Department of Biomedical Engineering, Boston University, Boston, United States of America

5Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, United States of America

6Ksilink, Strasbourg, France

7Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

8Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

9Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

10Department of Medicine, University of Alberta, Edmonton, Canada

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1Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Department of Genetics, Harvard Medical School, Boston, United States of America

3Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, United States of America

4Department of Biomedical Engineering, Boston University, Boston, United States of America

5Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, United States of America

6Ksilink, Strasbourg, France

7Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

8Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

9Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

10Department of Medicine, University of Alberta, Edmonton, Canada

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1Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Department of Genetics, Harvard Medical School, Boston, United States of America

3Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, United States of America

4Department of Biomedical Engineering, Boston University, Boston, United States of America

5Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, United States of America

6Ksilink, Strasbourg, France

7Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

8Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

9Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

10Department of Medicine, University of Alberta, Edmonton, Canada

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1Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Department of Genetics, Harvard Medical School, Boston, United States of America

3Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, United States of America

4Department of Biomedical Engineering, Boston University, Boston, United States of America

5Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, United States of America

6Ksilink, Strasbourg, France

7Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

8Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

9Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

10Department of Medicine, University of Alberta, Edmonton, Canada

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1Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Department of Genetics, Harvard Medical School, Boston, United States of America

3Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, United States of America

4Department of Biomedical Engineering, Boston University, Boston, United States of America

5Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, United States of America

6Ksilink, Strasbourg, France

7Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

8Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

9Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

10Department of Medicine, University of Alberta, Edmonton, Canada

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1Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Department of Genetics, Harvard Medical School, Boston, United States of America

3Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, United States of America

4Department of Biomedical Engineering, Boston University, Boston, United States of America

5Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, United States of America

6Ksilink, Strasbourg, France

7Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

8Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

9Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

10Department of Medicine, University of Alberta, Edmonton, Canada

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1Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Department of Genetics, Harvard Medical School, Boston, United States of America

3Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, United States of America

4Department of Biomedical Engineering, Boston University, Boston, United States of America

5Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, United States of America

6Ksilink, Strasbourg, France

7Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

8Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

9Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

10Department of Medicine, University of Alberta, Edmonton, Canada

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1Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Department of Genetics, Harvard Medical School, Boston, United States of America

3Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, United States of America

4Department of Biomedical Engineering, Boston University, Boston, United States of America

5Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, United States of America

6Ksilink, Strasbourg, France

7Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

8Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

9Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

10Department of Medicine, University of Alberta, Edmonton, Canada

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1Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Department of Genetics, Harvard Medical School, Boston, United States of America

3Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, United States of America

4Department of Biomedical Engineering, Boston University, Boston, United States of America

5Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, United States of America

6Ksilink, Strasbourg, France

7Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

8Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

9Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

10Department of Medicine, University of Alberta, Edmonton, Canada

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Published December 17, 2024 - More info

J Clin Invest. https://doi.org/10.1172/JCI183353.
Copyright © 2024, Kim et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published December 17, 2024 - Version history
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Abstract

Heterozygous truncating variants in the sarcomere protein titin (TTN) are the most common genetic cause of heart failure. To understand mechanisms that regulate abundant cardiomyocyte TTN expression we characterized highly conserved intron 1 sequences that exhibited dynamic changes in chromatin accessibility during differentiation of human cardiomyocytes from induced pluripotent stem cells (hiPSC-CMs). Homozygous deletion of these sequences in mice caused embryonic lethality while heterozygous mice demonstrated allele-specific reduction in Ttn expression. A 296 bp fragment of this element, denoted E1, was sufficient to drive expression of a reporter gene in hiPSC-CMs. Deletion of E1 downregulated TTN expression, impaired sarcomerogenesis, and decreased contractility in hiPSC-CMs. Site-directed mutagenesis of predicted NKX2-5- and MEF2-binding sites within E1 abolished its transcriptional activity. Embryonic mice expressing E1 reporter gene constructs validated in vivo cardiac-specific activity of E1 and the requirement for NKX2-5 and MEF2 binding sequences. Moreover, isogenic hiPSC-CMs containing a rare E1 variant in the predicted MEF2 binding motif that was identified in a patient with unexplained DCM showed reduced TTN expression. Together these discoveries define an essential, functional enhancer that regulates TTN expression. Manipulation of this element may advance therapeutic strategies to treat DCM caused by TTN haploinsufficiency.

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