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

## TL;DR

This study explores how chromatin architecture in human heart cells helps explain the role of non-coding DNA in heart diseases like arrhythmias.

## Contribution

The study identifies chamber-specific chromatin interactions in cardiomyocytes and links them to disease-associated genetic variants.

## Key findings

- Atrial and ventricular cardiomyocytes have distinct CRE-promoter interactions that influence gene expression.
- CREs containing QT-duration-associated variants modulate KCNJ2 gene expression and affect cardiomyocyte repolarization.
- Functional epigenetic silencing confirmed the role of CREs in regulating potassium channel activity in heart cells.

## 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.

Here the authors functionally test and resolve the spatial genome organization of cis-regulatory elements and genetic variants in atrial, ventricular, and failing human cardiomyocytes and linked them to heart disease traits, including QT syndrome.