Distinct cardiac transcriptomic clustering in titin and lamin a/c-associated dilated cardiomyopathy patients
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE146621 | GEO | 2021/03/09
REPOSITORIES: GEO
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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: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:Titintruncating variants(TTNtv) have been identified as the single largestgenetic cause of dilated cardiomyopathy(DCM). In this studywe modeled the disease phenotypes of TTNtv-induced DCM in hiPSC-CMsusing CRISPR/Cas9 genome editing and tissue engineering technologies. Transcriptomic, cellular and micro-tissue studies revealed that TTNtv hiPSC-CMs displayed pathogenic proteinopathy, sarcomere defects, aberrant Na+channel activities and, most importantly, contractile dysfunction. These phenotypes establish a dual mechanism of poison peptide effect and haploinsufficiency that collectively contribute to DCM pathogenesis. On the other hand, TTNtv cellular defects did not interfere with normal function of the core contractile machinery, actin-myosin-troponin-Ca2+complex, and preserved the therapeutic mechanism of sarcomere modulators. Treatment of TTNtv cardiac micro-tissues with investigational sarcomere modulators augmented contractility and resulted in sustained transcriptomicchanges that promotereversalof DCM disease signatures, as revealed by single-cell RNA-seqanalysis.Taken together, our findings depict the underlying pathogenic mechanisms of TTNtv-induced DCMand demonstrate the validity of sarcomere modulators as potentialtherapeutic agentsfor this disease.
2023-01-25 | GSE183217 | GEO
Project description:Titintruncating variants(TTNtv) have been identified as the single largestgenetic cause of dilated cardiomyopathy(DCM). In this studywe modeled the disease phenotypes of TTNtv-induced DCM in hiPSC-CMsusing CRISPR/Cas9 genome editing and tissue engineering technologies. Transcriptomic, cellular and micro-tissue studies revealed that TTNtv hiPSC-CMs displayed pathogenic proteinopathy, sarcomere defects, aberrant Na+channel activities and, most importantly, contractile dysfunction. These phenotypes establish a dual mechanism of poison peptide effect and haploinsufficiency that collectively contribute to DCM pathogenesis. On the other hand, TTNtv cellular defects did not interfere with normal function of the core contractile machinery, actin-myosin-troponin-Ca2+complex, and preserved the therapeutic mechanism of sarcomere modulators. Treatment of TTNtv cardiac micro-tissues with investigational sarcomere modulators augmented contractility and resulted in sustained transcriptomicchanges that promotereversalof DCM disease signatures, as revealed by single-cell RNA-seqanalysis.Taken together, our findings depict the underlying pathogenic mechanisms of TTNtv-induced DCMand demonstrate the validity of sarcomere modulators as potentialtherapeutic agentsfor this disease.
2023-01-25 | GSE183216 | GEO
Project description:Human patients carrying genetic mutations in RBM20 develop a clinically aggressive dilated cardiomyopathy (DCM) characterized by early onset heart failure, high mortality, and sudden death, which is recapitulated in animal models. RBM20 has two primary domains, an RNA recognition motif (RRM) that binds RNA and an arginine/serine (RS)-rich domain that mediates spliceosome assembly and nuclear localization. Reported data showed that mutations in the RS domain lead to severe DCM. Loss of the RRM domain in RBM20 has been shown to disrupt the splicing of RBM20 target transcripts but does not lead to DCM. The objectives of the present study were to determine the functional role of the RS domain in DCM and examine the mechanisms. Mice expressing RBM20 lacking the RS domain (Rbm20ΔRS) were generated using CRISPR/Cas9 technology. Male and female Rbm20ΔRS mice developed a DCM-like phenotype characterized by ventricular dilation and impaired systolic function, that is more severe in females. Splicing of RBM20 target genes, including Ttn, was disrupted in both Rbm20ΔRS and Rbm20ΔRRM mice. However, RBM20 was mis-localized to the sarcoplasm only in the hearts of Rbm20ΔRS mice, indicating that mis-localization of RBM20 rather than disrupted splicing is key in DCM pathogenesis.
2023-01-02 | GSE212799 | 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:To gain insights into the molecular pathogenesis of DCM caused by LMNA mutation, a doxycycline-inducible (Dox-Off) gene expression system was used to express either a wild type (WT) or a mutant LMNA containing the pathogenic variant p.Asp300Asn (LMNAD300N) in cardiac myocytes. The LMNAD300N is associated with DCM in patients with atypical progeroid/Werner syndrome and non-syndromic cardiac progeria. Expression of the mutant LMNAD300N protein in cardiac myocytes led to severe fibrosis, apoptosis, cardiac dysfunction, and premature death. RNA-seq was performed (prior to onset of cardiac dysfunction) to identify gene signatures and transcriptional regulators responsible for this phenotype. Mechanistic studies identified activation of E2F/TP53/DDR, as a major mechanism responsible for the pathogenesis of DCM caused by the LMNAD300N mutation.
2019-04-17 | GSE123916 | 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:Background: RBM20 gene is one of the genetic predispositions for dilated cardiomyopathy (DCM). Variants in RS domain has been reported in many DCM patients, while the pathogenicity of variants within the RNA-recognition motif remains unknown. Methods and results: We detected two human patients of I536T-RBM20 variant without DCM phenotype in sudden death cohorts. We performed splicing reporter assay and generated I538T knock-in (KI) mouse model (Rbm20I538T) in order to reveal the significance of this variant. The reporter assay revealed that human I536T variant affected TTN splicing pattern compared to wild-type. In the mouse experiments, Rbm20I538T mice presented a different splicing pattern in Ttn, Ldb3, Camk2d and Ryr2. The expression of Casq1, Mybpc2 and Myot were upregulated in Rbm20I538T mice. Whereas, Rbm20I538T mice did show neither DCM nor cardiac dysfunction by histopathological examination and ultrasound echocardiography. Conclusion: I536T-RBM20 (I538T-Rbm20) variant does not cause DCM phenotype, but changes the gene splicing and expression effect. The splicing and expression changes in Ttn and Ca handling genes such as Casq1, Camk2d and Ryr2 may be contributory to sudden arrhythmogenic death.
2022-10-05 | GSE201018 | GEO