Mutations in the nuclear A-type lamins- (LMNA gene) and dystrophin (DMD gene)-encoding genes cause dilated cardiomyopathy, characterized by compromised cardiac contractility resulting in poor left ventricular function and associated with a high incidence of conduction defects and arrhythmias. A physical continuum links the extracellular environment to the nuclear interior, crucial for mechanotransduction and structural support. Key components include the LINC complex, connecting the nuclear envelope to the cytoskeleton; dystrophin (DMD gene), linking actin to the basal membrane; and nuclear lamins A/C (LMNA gene), linking the LINC complex to chromatin.

Disruptions in these components in cardiomyocytes, as seen in DMD or LMNA gene mutations, can impair mechanotransduction, leading to genome conformation changes and dysregulated cardiac gene expression, ultimately contributing to dilated cardiomyopathy pathogenesis.

To address this question, we have examined relevant in vitro and in vivo models corresponding to each mutation associated with the disease.

Abnormal diastolic calcium levels and contractions have been observed in human induced pluripotent stem cell-derived cardiomyocytes (hiPSCs-CMs), along with impaired cardiac function in mice. Calcium modulation plays a crucial role in gene expression, particularly in cardiac remodeling. Additionally, global changes in genome organization may contribute to conduction defects by deregulating the expression of ion channel genes. To establish correlations between functional and structural abnormalities observed in hiPSCs-CMs and mice, we are investigating three-dimensional genome organization at various scales (chromosome, compartments, nucleosome, gene) using multi-omics and fluorescent in situ hybridization (FISH) approaches.

Integrating functional and genomic studies aims to enhance our understanding of the pathogenesis of dilated cardiomyopathy associated with LMNA and DMD gene mutations, shedding light on common molecular signatures and/or specific molecular characteristics.