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| Status |
Public on Jul 17, 2020 |
| Title |
Dysregulation of PDGFRB contributes to the pathogenesis of LMNA-related dilated cardiomyopathy |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Purpose: LMNA-DCM accounts for 5-10% of DCM cases and has an age-related penetrance whose onset typically appears between the ages of 30 and 40. However, the precise mechanisms linking the LMNA mutation to increased arrhythmogenicity are still unknown.
Methods: We utilized human iPSC-CMs, hESC-CMs, and cardiac tissues with RNA-seq, ChIP-seq, and ATAC-seq technologies.
Results: The electrophysiological studies of iPSC-CMs identify the LMNA mutation as a cause of increased arrhythmogenicity in mutant iPSC-CMs through abnormal calcium homeostasis. We find that the mutations in LMNA disrupt the global chromatin conformation, resulting in hyper-activation of the platelet-derived growth factor (PDGF) signaling pathway in LMNA-mutant iPSC-CMs. Inhibition of the PDGF signaling pathway can rescue the arrhythmic phenotype of mutant iPSC-CMs.
Conclusions: These findings were corroborated in cardiac tissues from healthy and LMNA-DCM patients, thus confirming a novel mechanism of LMNA-DCM pathogenesis both in vitro and in vivo.
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| Overall design |
RNA-seq, ChIP-seq, and ATAC-seq of iPSC-CMs and hESC-CMs
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| |
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| Contributor(s) |
Lee J, Termglinchan V, Shao N, Wu JC |
| Citation missing |
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| |
| Submission date |
Jul 17, 2017 |
| Last update date |
Jul 25, 2021 |
| Contact name |
Joseph Wu |
| Organization name |
Stanford University School of Medicine
|
| Street address |
Stanford University School of Medicine
|
| City |
Stanford |
| State/province |
Carlifornia |
| ZIP/Postal code |
94305 |
| Country |
USA |
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| Platforms (3) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
| GPL17303 |
Ion Torrent Proton (Homo sapiens) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA394714 |
| SRA |
SRP112550 |
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