Chamber-specific chromatin architecture guides functional interpretation of disease-associated Cis-regulatory elements in human cardiomyocytes
Cis-regulatory elements (CREs) are noncoding DNA regions regulating cell-type-specific gene expression programs by interacting with distal gene promoters. Here, we aim to decode the function and spatial organization of CRE-promoter interactions in human cardiomyocytes. We analyzed the epigenome and chromatin interactions of human male atrial, ventricular, and failing cardiomyocytes. Atrial and ventricular cardiomyocytes harbored chamber-specific CRE-promoter interactions modulating gene expression as confirmed by functional epigenetic silencing. These CRE-promoter interactions explain the distinct contribution of non-coding genetic variants to atrial and ventricular diseases, such as dilated cardiomyopathy and arrhythmias. We dissected the prototypic KCNJ2 locus, encoding a potassium channel associated with ventricular arrhythmia susceptibility. Functional epigenetic silencing confirmed that CREs, harboring QT-duration-associated genetic risk factors, modulate KCNJ2 gene expression levels, alter KCNJ2-dependent channel currents, and affect cardiomyocyte repolarization. The presented human CM-specific chromatin interaction analysis provides key insights into regulatory mechanisms and aids in interpreting genetic risk factors.
Authors
- Pavankumar Videm (ORCID: https://orcid.org/0000-0002-5192-126X)
- Ralf Gilsbach (ORCID: https://orcid.org/0000-0002-0895-1535)
- Niels Voigt (ORCID: https://orcid.org/0000-0001-8230-2341)
- Izzatullo Sobitov (ORCID: https://orcid.org/0000-0002-2737-4956)
- Sara Haydar (ORCID: https://orcid.org/0000-0003-0795-1733)
- H W Lahm
- B. A. Grüning
- M. Krane
- K. Streckfuss-Bömeke
- M. Dreßen
- S. Kuß
- N. Díaz i Pedrosa
- T. Lueneburg
- C. Schmidt
Institutions
- Goethe University Frankfurt (DE)
- University of Freiburg (DE)
- Heidelberg University (DE)
- University of Würzburg (DE)
- University Hospital Heidelberg (DE)
- German Center for Infection Research (DE)
- Universitätsmedizin Göttingen (DE)
- German Centre for Cardiovascular Research (DE)
- Deutsches Herzzentrum München (DE)
- University of Göttingen (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-01-12
- DOI
- https://doi.org/10.1038/s41467-025-67220-7
- Primary Topic
- Cardiac electrophysiology and arrhythmias
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Baden-Württemberg Stiftung
- Deutsches Zentrum für Herz-Kreislaufforschung
- European Molecular Biology Laboratory
- Universitätsmedizin Göttingen
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- Albert-Ludwigs-Universität Freiburg
- Technische Universität München
- German Network for Bioinformatics Infrastructure
- National Institutes of Health
- National Heart, Lung, and Blood Institute
- National Institute of Mental Health
- National Institute on Drug Abuse
- National Human Genome Research Institute
- NIH Office of the Director
- National Cancer Institute
- National Institute of Neurological Disorders and Stroke
- National Center for Advancing Translational Sciences
- Common Fund