The cytoskeleton drives abnormal chromatin-lamina interactions in LMNA-deficient cardiomyocytes.

Spatial organization of chromatin at the nuclear lamina is critical for cellular identity, but mechanisms governing genome-lamina interactions remain unresolved. In particular, it remains unclear if and how mechanical inputs impact genome-lamina interactions. We modeled aspects of laminopathies via siRNA-mediated lamin A/C (LMNA) knockdown to examine how the nuclear lamina and cytoskeleton contribute to loss of lamina-associated domain (LAD) organization. Genomics and imaging analyses reveal spatial positioning of LADs with a specific molecular signature are particularly vulnerable to LMNA reduction. Further, a subset of these LADs retain their lamina-association with either concomitant disruption of the Linker of Nucleoskeleton and Cytoskeleton complex or microtubule depolymerization. Conversely, microtubule stabilization phenocopies spatial positioning changes observed in LMNA-knockdown cells. These data suggest peripheral chromatin organization is regulated by the balance of nuclear lamina and cytoskeletal interactions across the nuclear membrane. In the context of a compromised nuclear lamina, such as LMNA reduction, the cytoskeleton contributes to loss of peripheral chromatin organization.