The K219T-Lamin mutation induces conduction defects through epigenetic inhibition of SCN5A in human cardiac laminopathy
NATURE COMMUNICATIONS(2019)
Abstract
Mutations in LMNA , which encodes the nuclear proteins Lamin A/C, can cause cardiomyopathy and conduction disorders. Here, we employ induced pluripotent stem cells (iPSCs) generated from human cells carrying heterozygous K219T mutation on LMNA to develop a disease model. Cardiomyocytes differentiated from these iPSCs, and which thus carry K219T- LMNA , have altered action potential, reduced peak sodium current and diminished conduction velocity. Moreover, they have significantly downregulated Na v 1.5 channel expression and increased binding of Lamin A/C to the promoter of SCN5A , the channel’s gene. Coherently, binding of the Polycomb Repressive Complex 2 (PRC2) protein SUZ12 and deposition of the repressive histone mark H3K27me3 are increased at SCN5A . CRISPR/Cas9-mediated correction of the mutation re-establishes sodium current density and SCN5A expression. Thus, K219T- LMNA cooperates with PRC2 in downregulating SCN5A , leading to decreased sodium current density and slower conduction velocity. This mechanism may underlie the conduction abnormalities associated with LMNA-cardiomyopathy.
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Key words
Cardiomyopathies,Induced pluripotent stem cells,Mechanisms of disease,Science,Humanities and Social Sciences,multidisciplinary
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