The K219T-Lamin mutation induces conduction defects through epigenetic inhibition of SCN5A in human cardiac laminopathy
Articolo
Data di Pubblicazione:
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 Nav1.5 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.
Tipologia CRIS:
03A-Articolo su Rivista
Keywords:
Adolescent; Adult; Cardiomyopathy, Dilated; Cell Line; Down-Regulation; Epigenesis, Genetic; Female; Heart Conduction System; Heart Transplantation; Humans; Induced Pluripotent Stem Cells; Lamin Type A; Male; Middle Aged; Mutation; Myocardium; Myocytes, Cardiac; NAV1.5 Voltage-Gated Sodium Channel; Polycomb Repressive Complex 2
Elenco autori:
Salvarani N.; Crasto S.; Miragoli M.; Bertero A.; Paulis M.; Kunderfranco P.; Serio S.; Forni A.; Lucarelli C.; Dal Ferro M.; Larcher V.; Sinagra G.; Vezzoni P.; Murry C.E.; Faggian G.; Condorelli G.; Di Pasquale E.
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