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<p><i>Cis-</i>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 <i>KCNJ2</i> locus, encoding a potassium channel associated with ventricular arrhythmia susceptibility. Functional epigenetic silencing confirmed that CREs, harboring QT-duration-associated genetic risk factors, modulate <i>KCNJ2</i> 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.</p>

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Chamber-specific chromatin architecture guides functional interpretation of disease-associated Cis-regulatory elements in human cardiomyocytes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月12日

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  • 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

摘要

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.