Spatial organizations of heterochromatin underpin nuclear structural integrity of ventricular cardiomyocytes against mechanical stress.

Cardiomyocyte (CM) nuclei are constantly exposed to mechanical stress, but how they maintain their nuclear shape remains unknown. In this study, we found that ventricular CM nuclei acquire characteristic prominent spatial organizations of heterochromatin (SOH), which are disrupted by high-level expression of H2B-mCherry in mice. SOH disruption was associated with nuclear softening, leading to extreme elongation and rupture under unidirectional mechanical stress. Loosened chromatin then leaks into the cytosol, causing severe inflammation and cardiac dysfunction. Although SOH disruption was accompanied by loosened higher-order genomic structures, the change in gene expression before nuclear deformation was mild, suggesting that SOH play major roles in nuclear structural integrity. Aged CM nuclei consistently exhibited scattered SOH and marked elongation. Furthermore, we provide mechanistic insight into the development and maintenance of SOH driven by chromatin compaction and condensate formation. These results highlight SOH as a safeguard of nuclear shape and genomic integrity against mechanical stress. [Display omitted] • Cardiomyocytes acquire characteristic spatial organizations of heterochromatin (SOH) • High levels of H2B-mCherry disrupt SOH, leading to nuclear elongation in cardiomyocytes • SOH disruption minimally impacts gene expression despite loosening global genome structure • SOH alter with aging, leading to nuclear deformation in ventricular cardiomyocytes Cardiomyocytes exhibit characteristic prominent spatial organizations of heterochromatin (SOH). Fujiwara et al. found that the replacement of endogenous H2B with H2B-mCherry disrupts SOH, leading to extreme elongation of ventricular cardiomyocyte nuclei, resulting in severe heart failure, demonstrating that SOH play a structural role in maintaining nuclear shape against mechanical stress. [ABSTRACT FROM AUTHOR]