Molecular insights into the role of desmin intermediate filament network in chromatin landscape, cardiomyocyte differentiation, and maturation.

The cardiac cytoskeleton is essential for the proper intracellular and intercellular integration of cardiomyocyte structure, maintenance and function, failure of which leads to cell death and heart disease. In particular, the desmin intermediate filament cytoskeleton, due to its early expression and subcellular distribution, enables the formation of a continuous network that connects the extracellular space with the nuclear matrix, thus allowing us to hypothesize potential key roles in mechanotransduction to the nucleus, and consequently, in cardiac lineage determination, differentiation and development. Here, we investigated the role of desmin in cardiac differentiation and homeostasis across embryogenesis, postnatal life, and adulthood, as well as under various stimuli. Desmin was found to be highly expressed in cardiac progenitor cells during embryogenesis, and its absence significantly impacts the size of this population. Using direct cellular reprogramming of fibroblasts to induced cardiomyocytes, we demonstrated that ectopic desmin expression directly influences cardiomyogenesis, potentially linked, among others, to transcriptional regulation of the Notch1 signaling. Conversely, desmin deficiency leads to substantial perturbations in cardiac maturation by diminishing the expression and proper localization of cardiac-specific proteins, impairing calcium homeostasis and delaying myofibril formation. RNA and ChIP sequencing, coupled with Hi-C analysis, revealed that desmin depletion causes chromatin architectural disruptions, altering genome organization and gene expression of cardiac-specific modulators, contributing to pathophysiological phenotype.