Lamin C supplementation as therapeutic target for treatment of Lmna Dilated Cardiomyopathy (DCM) and risk of Lamin A toxicity
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ABSTRACT:
PROVIDER: PRJNA1005183 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25634963_1.fastq.gz | Fastqsanger.gz | |||
| SRR25634963_2.fastq.gz | Fastqsanger.gz | |||
| SRR25634964_1.fastq.gz | Fastqsanger.gz | |||
| SRR25634964_2.fastq.gz | Fastqsanger.gz | |||
| SRR25634965_1.fastq.gz | Fastqsanger.gz |
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Project description:Dilated cardiomyopathy (DCM) is a severe, non-ischemic heart disease, which ultimately results in heart failure (HF). Pathological genetic variants in LMNA cause DCM, which currently lacks specific treatment. Perturbing candidates related to dysregulated pathways have shown to ameliorate LMNA DCM, but their long-term efficacy as potential therapeutic targets is unknown. Here, we evaluated 14 potential candidates including Lmna gene products, key signaling pathways, calcium handling, proliferation regulators and Lamin interacting proteins, in a cardiac-specific Lmna DCM model. The candidates with improved cardiac function were further assessed through survival analysis. After comparing cardiac function, marker gene expression, Tgfβ signaling pathway activation, fibrosis, inflammation, proliferation, and DNA damage, we uncovered that restored cardiac function significantly correlated with suppression of HF/fibrosis marker expression and cardiac fibrosis in Lmna DCM. Interestingly, Lamin C or Sun1 shRNA administration achieved consistent, prolonged survival which highly correlated with reduced heart inflammation and DNA damage. In addition to Sun1 shRNA, perturbing the interaction between the nucleoskeleton and cytoskeleton via the KASH domain of Nesprin1 also effectively suppressed Lmna DCM. In contrast, Lamin A supplementation did not rescue long term survival and may impart a detrimental cardiotoxicity risk. Furthermore, transcriptome profiling was used to compare the differences between Lamin A and Lamin C treatment. Mechanistically, we identified that this lapse was attributed to a dose-dependent toxicity of Lamin A, which was independent of its maturation. This study highlights the potential for advancing Lamin C and Sun1 as therapeutic targets for the treatment of LMNA DCM.
2024-08-11 | GSE240745 | GEO
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
Project description:Mutation of the LMNA gene, encoding nuclear lamin A and lamin C (hereafter lamin A/C), is a common cause of familial dilated cardiomyopathy (DCM). Among Finnish DCM patients, the founder mutation c.427T>C (p.S143P) is the most frequently reported genetic variant. Here, we show that p.S143P lamin A/C is more nucleoplasmic and soluble than wild-type lamin A/C and accumulates into large intranuclear aggregates in a fraction of cultured patient fibroblasts as well as in cells ectopically expressing either FLAG- or GFP-tagged p.S143P lamin A. In fluorescence loss in photobleaching (FLIP) experiments, non-aggregated EGFP-tagged p.S143P lamin A is significantly more dynamic. In in vitro association studies, p.S143P lamin A failed to form appropriate filament structures but instead assembled into disorganized aggregates similar to those observed in patient cell nuclei. A whole genome expression analysis revealed an elevated unfolded protein response (UPR) in cells expressing p.S143P lamin A/C. Additional endoplasmic reticulum (ER) stress induced by tunicamycin reduced the viability of mutant lamin expressing cells further. In summary, p.S143P lamin A/C affects normal lamina structure and influences the cellular stress response, homeostasis and viability. Total RNA obtained from 4 control and 7 patient cell lines
2016-06-10 | E-GEOD-82290 | biostudies-arrayexpress
Project description:Mutations of the lamin A/C gene (LMNA) cause a variety of diseases including dilated cardiomyopathy (DCM). LMNA-related DCM often leads to severe heart failure, but the underlying pathophysiology is unknown. Here we show that vitamin D receptor (VDR) signaling is critically involved in LMNA-related DCM. We established iPS cells from DCM patients with an LMNA mutation and found that the iPS cell-derived cardiomyocytes (iPSCMs) showed remarkable DNA damage and reduced contractility compared with the isogenic control. Screening of a chemical library revealed that vitamin D2 reduced DNA damage of the mutant iPSCMs. RNA sequencing analysis showed that expression levels of putative downstream genes of VDR including DNA repair factors were downregulated in the mutant iPSCMs, which were upregulated by vitamin D2. Protein-protein interaction screening revealed that the binding of VDR to mutant LMNA was more robust than to wild-type LMNA, resulting in attenuated VDR signaling in the mutant iPSCMs. Vitamin D2 administration reduced DNA damage and improved cardiac function in pressure overload-induced heart failure mice. These results indicate that impaired DNA repair caused by reduced transcriptional activity of VDR induces cardiac dysfunction of LMNA-related DCM and suggest that VDR signaling is a potential therapeutic target for patients with DCM and heart failure.
2025-03-01 | GSE182219 | GEO
Project description:Mutations in the LMNA gene causes set of disorders collectively referred to as laminopathies that include dilated cardiomyopathy. Lamin A/C proteins a components of nuclear lamina forms distinct nuclear domains called lamina associated domains (LADs). The roles of LADs in DCM is not known. To identify LADs and characterize their associations with CpG methylation and gene expression in human cardiac myocytes isolated from patients with DCM and controls we performed Chromatin immunoprecipitation-sequencing (ChIP-Seq), reduced representative bisulfite sequencing (RRBS), and RNA-sequencing (RNA-Seq) in 5 control and 5 DCM hearts with defined pathogenic variants in the LMNA gene. LADs are redistributed in DCM, are associated with CpG methylation and suppressed transcription, contributing to the pathogenesis of DCM in laminopathies.
2019-03-12 | GSE120837 | GEO
Project description:Mutations in the LMNA gene causes set of disorders collectively referred to as laminopathies that include dilated cardiomyopathy. Lamin A/C proteins a components of nuclear lamina forms distinct nuclear domains called lamina associated domains (LADs). The roles of LADs in DCM is not known. To identify LADs and characterize their associations with CpG methylation and gene expression in human cardiac myocytes isolated from patients with DCM and controls we performed Chromatin immunoprecipitation-sequencing (ChIP-Seq), reduced representative bisulfite sequencing (RRBS), and RNA-sequencing (RNA-Seq) in 5 control and 5 DCM hearts with defined pathogenic variants in the LMNA gene. LADs are redistributed in DCM, are associated with CpG methylation and suppressed transcription, contributing to the pathogenesis of DCM in laminopathies.
2019-03-12 | GSE120836 | GEO
Project description:Mutation of the LMNA gene, encoding nuclear lamin A and lamin C (hereafter lamin A/C), is a common cause of familial dilated cardiomyopathy (DCM). Among Finnish DCM patients, the founder mutation c.427T>C (p.S143P) is the most frequently reported genetic variant. Here, we show that p.S143P lamin A/C is more nucleoplasmic and soluble than wild-type lamin A/C and accumulates into large intranuclear aggregates in a fraction of cultured patient fibroblasts as well as in cells ectopically expressing either FLAG- or GFP-tagged p.S143P lamin A. In fluorescence loss in photobleaching (FLIP) experiments, non-aggregated EGFP-tagged p.S143P lamin A is significantly more dynamic. In in vitro association studies, p.S143P lamin A failed to form appropriate filament structures but instead assembled into disorganized aggregates similar to those observed in patient cell nuclei. A whole genome expression analysis revealed an elevated unfolded protein response (UPR) in cells expressing p.S143P lamin A/C. Additional endoplasmic reticulum (ER) stress induced by tunicamycin reduced the viability of mutant lamin expressing cells further. In summary, p.S143P lamin A/C affects normal lamina structure and influences the cellular stress response, homeostasis and viability.
2016-06-10 | GSE82290 | GEO
Project description:Lamins are type V intermediate filament proteins underlying the inner nuclear membrane which provide structural rigidity to the nucleus, tether the chromosomes and maintain nuclear homeostasis. Studies have identified developmentally regulated regions of the genome that are dynamically associated with the nuclear lamina. A large number of mutations in LMNA gene encoding lamin A/C results in a wide array of human diseases, collectively termed as laminopathies. Dilated Cardiomyopathy (DCM) is one such cardiovascular disease which is associated with systolic dysfunction of left or both ventricles leading to cardiac arrhythmia culminating into myocardial infarction. In this work, we have unravelled the gene expression by RNA Sequencing analysis in mouse myoblast cell line in the context of the missense mutation LMNA 289A>G (Lys97Glu) that is found in DCM afflicted patients with severe symptoms.
2022-06-26 | GSE206759 | GEO
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
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