A gene regulatory element modulates myosin expression and controls cardiomyocyte response to stress
- Taylor Anglen1,2,
- Irene M. Kaplow2,3,10,
- Baekgyu Choi4,
- Enya Dewars1,
- Robin M. Perelli1,
- Kevin T. Hagy2,3,
- Duc Tran1,2,
- Megan E. Ramaker5,
- Svati H. Shah5,6,
- Inkyung Jung4,
- Andrew P. Landstrom1,7,
- Ravi Karra6,8,9,
- Yarui Diao1,2 and
- Charles A. Gersbach1,2,3
- 1Department of Cell Biology, Duke University School of Medicine, Durham, North Carolina 27708, USA;
- 2Center for Advanced Genomic Technologies, Duke University, Durham, North Carolina 27708, USA;
- 3Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, USA;
- 4Department of Biological Science, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea;
- 5Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina 27708, USA;
- 6Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina 27708, USA;
- 7Division of Cardiology, Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina 27708, USA;
- 8Department of Medicine, Duke University School of Medicine, Durham, North Carolina 27708, USA;
- 9Department of Pathology, Duke University School of Medicine, Durham, North Carolina 27708, USA
Abstract
A hallmark of heart disease is gene dysregulation and reactivation of fetal gene programs. Reactivation of these fetal programs has compensatory effects during heart failure, depending on the type and stage of the underlying cardiomyopathy. Thousands of putative cardiac gene regulatory elements have been identified that may control these programs, but their functions are largely unknown. Here, we profile genome-wide changes to gene expression and chromatin structure in cardiomyocytes derived from human pluripotent stem cells. We identify and characterize a gene regulatory element essential for regulating MYH6 expression, which encodes human fetal myosin. Using chromatin conformation assays in combination with epigenome editing, we find that gene regulation is mediated by a direct interaction between MYH6 and the enhancer. We also find that enhancer activation alters cardiomyocyte response to the hypertrophy-inducing peptide endothelin-1. Enhancer activation prevents polyploidization as well as changes in calcium dynamics and metabolism following stress with endothelin-1. Collectively, these results identify regulatory mechanisms of cardiac gene programs that modulate cardiomyocyte maturation, affect cellular stress response, and could serve as potential therapeutic targets.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.280825.125.
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Freely available online through the Genome Research Open Access option.
- Received April 21, 2025.
- Accepted September 25, 2025.
This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
