The Nucleus Mediates Mechanosensitive Reorganization of Epigenetically Marked Chromatin During Cardiac Maturation and Pathology

摘要: Mechanical stimuli are essential to guide cell differentiation, but little is understood about the underlying mechanisms. The nucleus thought integrate mechanical signals through complexes that physically connect nucleoskeleton cytoskeleton and exposome; however, direct evidence of nuclear mechanosensation sparse, its role in guiding differentiation unclear. Here we investigated changes chromatin organization during cardiac development disease, analyzed how contraction-generated strains impacted reorganization. We found contractile cardiomyocytes adopt a distinct architecture was driven by reorganization H3K9me3-modified chromatin. Degenerative (stiff) environments inhibited deformation abrogated formation maintenance vitro vivo, promoted H3K27me3-modified instead. By generating high-resolution maps intranuclear exerted contraction, further isolated tensile hydrostatic, not shear or deviatoric, guided rearrangement H3K9me3-marked Moreover, disruption LINC (Linker Nucleo- Cytoskeleton) reorganization, epigenetic regulation as observed stiff environments. Subsequent analysis revealed complementary mechanosensitive pathways (e.g. via stretch p130Cas located within sarcomeric Z-disk) regulate mediators. Together, our findings provide novel for show environmental mechanics can influence epigenetically-modified pathways.