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Dysregulation of PDGFRB contributes to the pathogenesis of LMNA-related dilated cardiomyopathy [ChIP-seq]

ABSTRACT: 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 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE118884 | GEO | 2019/07/05

REPOSITORIES: GEO

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Dysregulation of PDGFRB contributes to the pathogenesis of LMNA-related dilated cardiomyopathy

Project description: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.

2020-07-17 | GSE101514 | GEO

Dysregulation of PDGFRB contributes to the pathogenesis of LMNA-related dilated cardiomyopathy [ATAC-seq]

Project description: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 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.

2019-07-05 | GSE118883 | GEO

Dysregulation of PDGFRB contributes to the pathogenesis of LMNA-related dilated cardiomyopathy [RNA-seq]

Project description: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 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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2015-02-09 | E-GEOD-65762 | biostudies-arrayexpress

Project description:LMNA-Related DCM involves cardiomyocyte dysfunction resulting in heart failure or sudden death. It is caused by LMNA mutations encoding Lamin A/C defects involved in nuclear integrity and gene expression. To investigate possible mechanisms, we used iPSC derived from a LMNA c.357-2A>G Patient and her unaffected sister. We differentiated iPSC and conducted scRNA-seq for 4 Patient and 8 Control samples across seven time points from Day 0 to 30. Using a comprehensive bioinformatics workflow, we identified 110,521 high-quality cells and complex heterogeneity: ten main cell types, possible subtypes, and lineage bifurcation for Cardiac Progenitors to Cardiomyocytes and Epicardium-Derived Cells (EPDC). By comparative analyses, we found differentially expressed genes (DEG) and enrichment supporting pathway dysregulation for ZNF genes and RNA polymerase II transcription in Pluripotent cells; BMP4 and TGF Beta/BMP signaling, sarcomere genes and cardiogenesis, CDH2 and EMT in Cardiomyocytes; LMNA and epigenetic regulation and DDIT4 and mTORC1 signaling in EPDC. In addition, top DEG included XIST, six imprinted genes, and gene sets in metabolism, proliferation, and homeostasis. We confirmed Lamin A/C haploinsufficiency by allelic expression and Western blot. Our evidence supports disruption of epigenomic developmental programs in LMNA-Related DCM and also demonstrates current challenges of LMNA disease modeling using Patient-derived iPSC.

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Expression data from E161K LMNA mutant heart and control

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TEAD1 trapping by the Q353R-Lamin A/C causes dilated cardiomyopathy.

Project description:• Mutations in the LMNA gene encoding Lamin A and C (Lamin A/C), major components of the nuclear lamina, cause laminopathies including dilated cardiomyopathy (DCM), but the underlying molecular mechanisms have not been fully elucidated. Here, by leveraging single-cell RNA-seq, ATAC-seq, protein array, and electron microscopy analysis, we show that insufficient structural maturation of cardiomyocytes owing to trapping of transcription factor TEAD1 by mutant Lamin A/C at the nuclear membrane underlies the pathogenesis of Q353R- LMNA-related DCM. Inhibition of the Hippo pathway rescued the dysregulation of cardiac developmental genes by TEAD1 in LMNA-mutant cardiomyocytes. Single-cell RNA-seq of cardiac tissues from DCM patients with the LMNA mutation confirmed the dysregulated expression of TEAD1 target genes. Our results propose an intervention for transcriptional dysregulation as a potential treatment of LMNA-related DCM.

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