Linking Chamber-Specific Spatial Chromatin Interactions to Disease Variants and Gene Programs in Human Cardiomyocytes

Abstract Cell-type specific gene expression programs and response to stimuli are modulated by cis-regulatory elements (CREs). CREs modulate the activity of spatially interacting gene promoters. Heart disease is a major cause of death worldwide. Here, we aim to decode CRE-promoter interactions in atrial and ventricular cardiomyocytes and link them to heart disease and genetic risk factors. Therefore, we analyze the epigenetic features and chromatin interactions of human atrial, ventricular, and failing cardiomyocytes (CM). In failing CM a limited number of genes, including NPPA, showed rewiring events orchestrating differential gene expression. Remarkably, we find that atrial and ventricular CM harbor chamber-specific chromatin interactions which are linked to gene expression indicating that chromatin organization underlies atrial and ventricular CM specification. The chamber-specific chromatin interactions also explain the contribution of non-coding genetic CRE variants to the occurrence of atrial and ventricular diseases, including atrial and ventricular arrhythmia. Functional silencing of CREs carrying genetic QT-duration risk factors confirmed their functional relevance. Our human CM data demonstrates that cell type-specific chromatin interaction analysis provides crucial insights into regulatory mechanisms and aids the interpretation of genetic risk factors identified in patients and association studies.