The cytoskeleton contributes to abnormal genome–lamina interactions in LMNA-deficient cardiomyocytes

The spatial organization of chromatin at the nuclear lamina contributes to genome structure and gene regulation. Mechanical inputs are increasingly recognized as key regulators of nuclear architecture, and understanding how they control genome–lamina interactions and influence diseases associated with the nuclear lamina remains unclear. To understand the role of lamin proteins and the cytoskeleton in peripheral chromatin organization and consider this role in the context of laminopathies, we performed siRNA-mediated partial knockdown of lamin A/C (LMNA) in human cardiomyocytes and examined lamina-associated domains (LADs). Genome-wide mapping and locus-specific imaging reveal that LADs with a distinct molecular signature are preferentially vulnerable to LMNA reduction. A subset of these sensitive LADs retain lamina association when the linker of nucleoskeleton and cytoskeleton complex (LINC) is disrupted or microtubules are depolymerized. These findings indicate that, in the context of a compromised nuclear lamina, cytoskeletal inputs transmitted through the LINC complex play a key role in the reorganization of peripheral chromatin.