Lamin A Regulates Chromatin Structure and Function in Cardiac Myocytes in a Mouse Model of Lamin-Cardiomyopathy

Abstract

Mutations in the LMNA gene, encoding lamin A (LMNA), cause laminopathies. Cardiac involvement is common and a major cause of mortality and morbidity in laminopathies. LMNA interacts with chromatin through lamin-associated domains (LADs) and regulates gene expression. We report that LMNA deficiency increased genome-wide CTCF occupancy, predominantly outside of the constitutive LAD (cLAD) regions. CTCF occupancy was associated with increased gene expression and enrichment of double-stranded breaks (DSBs). LMNA deficiency had a modest effect on chromatin compartments but led to mergers, splitting, and shifting boundaries of one-third of the topologically associated domains (TADs) without affecting gene expression significantly. LMNA deficiency led to a gain of ~ 600 and a loss of ~ 1000 loops, which were associated with increased and decreased transcript levels, respectively. Reorganization of chromatin loops affected ~25% of the differentially expressed genes in the LMNA-deficient cardiac myocytes. In multivariate analysis, CTCF binding sites, chromatin loops, and cLADs were independent predictors of gene expression in the LMNA-deficient cardiac myocytes, whereas TADs and chromatin compartments were not. Thus, LMNA deficiency changes genome-wide CTCF occupancy and loop organization, which affect gene expression in cardiac myocytes. The findings provide new insights into the pathogenesis of cardiac involvement in laminopathies.