Authors

Haydar S, Bednarz R, Laurette P, Sobitov I, Díaz I Pedrosa N, Videm P, Lueneburg T, Kuß S, Lahm H, Dreßen M, Krane M, Schmidt C, Grüning BA, Voigt N, Streckfuss-Bömeke K, Gilsbach R

Journal

Nature Communications

Citation

Nat Commun. 2026 Jan 12;17(1):117.

Abstract

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.

DOI

10.1038/s41467-025-67220-7
 
Pubmed Link