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Deletion of the Lmna Gene in Fibroblasts Causes Senescence-Associated Dilated Cardiomyopathy

ABSTRACT: Deletion of Lmna in PDGFRA+ cells cause dilated cardiomyoapthy.

ORGANISM(S): Mus musculus

PROVIDER: GSE199078 | GEO | 2022/06/09

REPOSITORIES: GEO

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Deletion of the Lmna Gene in Fibroblasts Causes Senescence-Associated Dilated Cardiomyopathy

Project description:Deletion of the Lmna Gene in Fibroblasts Causes Senescence-Associated Dilated Cardiomyopathy

| PRJNA818297 | ENA

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.

2023-03-06 | GSE190977 | GEO

Deletion of the <i>Lmna</i> gene in fibroblasts causes senescence-associated dilated cardiomyopathy by activating the double-stranded DNA damage response and induction of senescence-associated secretory phenotype.

Project description: Not available

| S-EPMC9311325 | biostudies-literature

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

The cGAS-STING pathway is dispensable in a mouse model of LMNA-cardiomyopathy despite nuclear envelope rupture [mRNA-seq]

Project description:Mutations in LMNA, encoding the nuclear lamina protein Lamin A/C, cause malignant dilated cardiomyopathy. A prevailing hypothesis postulates that LMNA mutations cause nuclear envelope ruptures that trigger pathogenic inflammation via the cGAS-STING cytosolic DNA-sensing pathway. Our study suggests that adult mouse cardiomyocytes are unable to activate the cGAS-STING pathway in response to nuclear envelope rupture and proposes that the cGAS-STING pathway is not a pathogenetic component of LMNA-related dilated cardiomyopathy in adult humans. The aim of this project is to investigate the contribution of the cGAS-STING cytosolic DNA-sensing pathway to a mouse model of LMNA-related dilated cardiomyopathy accompanied by nuclear envelope rupture.

2024-04-26 | GSE241577 | GEO

The cGAS-STING pathway is dispensable in a mouse model of LMNA-cardiomyopathy despite nuclear envelope rupture [sci-RNA-seq]

2024-04-26 | GSE241587 | GEO

The cGAS-STING pathway is dispensable in a mouse model of LMNA-cardiomyopathy despite nuclear envelope rupture [SLAM-IT-seq]

2024-04-26 | GSE241589 | GEO

Dysregulation of PDGFRB contributes to the pathogenesis of LMNA-related dilated cardiomyopathy [ChIP-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 | GSE118884 | 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.

2019-07-05 | GSE118882 | GEO

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