Key result
LMNA deficiency alters chromatin looping to disrupt expression of ~25% of differentially expressed genes.
Why the study?
Mutations in the LMNA gene cause laminopathies with common cardiac involvement that drives morbidity and mortality, and lamin A interacts with chromatin through lamin-associated domains to regulate gene expression.
Does LMNA deficiency alter chromatin structure, CTCF occupancy, and gene expression in cardiac myocytes in a mouse model of lamin-cardiomyopathy?
Does LMNA deficiency alter chromatin structure, CTCF occupancy, and gene expression in cardiac myocytes in a mouse model of lamin-cardiomyopathy?
In a mouse model of lamin-cardiomyopathy, LMNA deficiency alters genome-wide CTCF occupancy and chromatin loop organization, driving changes in cardiac myocyte gene expression and providing mechanistic insight into the pathogenesis of cardiac laminopathies.
LMNA-CTCF dysregulation in animal models may underlie laminopathy gene expression changes; leaves open relevance to human cardiac phenotypes pending validation.
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.
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Gurha et al. (2026) studied Lamin-cardiomyopathy (mouse model). LMNA deficiency was evaluated on Chromatin structure (CTCF occupancy, TADs, chromatin loops) and gene expression in cardiac myocytes. LMNA deficiency in mouse cardiac myocytes caused a gain of ~600 and loss of ~1000 chromatin loops, affecting ~25% of differentially expressed genes.
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