期刊
NATURE COMMUNICATIONS
卷 10, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-09929-w
关键词
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资金
- Italian Ministry of Health [GR-2011-02347743, PE-2013-02356818, PE-2011-02347329]
- Interomics Flagship Project of the CNR
- IO MERITO Project of the Humanitas Research Center
- EMBO Long-Term Fellowship [ALTF 448-2017]
- European Research Council Advanced Grant (CardioEpigen) [294609]
- CARIPLO Foundation [2015-0573]
- PNR-CNR Aging Program [PE-2011-02347329]
- Italian Ministry of Education, University and Research [2015583WMX]
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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