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

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.