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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...

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Auteurs principaux: Haydar, Shaza (Auteur) , Bednarz, Rebecca (Auteur) , Laurette, Patrick (Auteur) , Sobitov, I. (Auteur) , Díaz i Pedrosa, N. (Auteur) , Videm, Pavankumar (Auteur) , Lueneburg, T. (Auteur) , Kuß, S. (Auteur) , Lahm, H. (Auteur) , Dreßen, M. (Auteur) , Krane, Markus A. (Auteur) , Schmidt, C. (Auteur) , Grüning, B. A. (Auteur) , Voigt, N. (Auteur) , Streckfuss-Bömeke, Katrin (Auteur) , Gilsbach, Ralf (Auteur)
Format: Article (Journal)
Langue:anglais
Publié: 12 January 2026
In: Nature Communications
Year: 2026, Volume: 17, Pages: 1-21
ISSN:2041-1723
DOI:10.1038/s41467-025-67220-7
Accès en ligne:Resolving-System, kostenfrei, Volltext: https://doi.org/10.1038/s41467-025-67220-7
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-025-67220-7
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Notes sur l'auteur:S. Haydar, R. Bednarz, P. Laurette, I. Sobitov, N. Díaz i Pedrosa, P. Videm, T. Lueneburg, S. Kuß, H. Lahm, M. Dreßen, M. Krane, C. Schmidt, B.A. Grüning, N. Voigt, K. Streckfuss-Bömeke & R. Gilsbach
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Résumé: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.
Description:Gesehen am 13.05.2026
Description matérielle:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-025-67220-7

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