TEAD1 trapping by the Q353R-Lamin A/C causes dilated cardiomyopathy.
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE190977 | GEO | 2023/03/06
REPOSITORIES: GEO
Similar Datasets
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:Lamin A/C proteins, encoded by the LMNA gene, are intermediate filament proteins of the nuclear lamina, and predominantly expressed in differentiated cells including cardiomyocytes. Mutations in LMNA are associated with laminopathies, congenital diseases affecting muscle and homeostasis. One of the laminopathies associated with a missense mutation (N195K) in the A-type lamins results in dilated cardiomyopathy (DCM) with arrhythmias and sudden death. However it is unknown how the mutation in this LMNA gene contributes to the mechanism of arrhythmia and sudden death. To investigate this a mouse line expressing the Lmna-N195K (LmnaN195K/N195K) was used. Mutant mice demonstrated reduced fractional shortening, LV mass, wall thickness and dilated cardiomyopathy by echocardiography at 6 weeks consistent with human DCM, and died at an early age (6-7 weeks). Comparative cDNA microarray analysis from LmnaN195K/N195K and the wild type (WT) control ventricles at 6 weeks age revealed significant alterations in the expression of ion channels, transporter proteins, caveolins and associated proteins such as MAP kinases. Transmission electron microscopy analysis showed structural alterations of the ventricular myocytes with increase in number of caveolae. Quantitative Western blot analysis confirmed reduced expression for Cavβ (2 fold) subunits of the L-type Ca2+ channel. In contrast the expression levels of Cav3 (2.5 fold) was significantly increased. To investigate the functional impact of Lmna N195K on the ICa,L, we transiently expressed either the WT LMNA+GFP, Lmna N195K+GFP or GFP (control) in isolated neonatal mouse ventricular myocytes and performed whole cell patch clamp analysis. Transient expression of Lmna N195K significantly reduced (58 %) peak ICa,L (-6.0 ± 2 pA/pF, n=9) compared to GFP control (-14 ± 2 pA/pF, n=8). Expression of WT LMNA did not affect the ICa,L (-14.2 ± 2.5 pA/pF, n=8) compared to control. Conclusion: We conclude that Lmna N195K mutation results in reduced expression of ion channels and scaffolding proteins in the left ventricle with a significant reduction in peak ICa,L in ventricular myocytes and these may contribute to the mechanism of arrhythmia and dilated cardiomyopathy. 6 samples
2012-05-31 | E-GEOD-36502 | biostudies-arrayexpress
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:Background: Lamins A/C (encoded by the LMNA gene) can lead to dilated cardiomyopathy (DCM). Objectives: This study sought to undertake proteomic analysis of myocardial tissue to explore the postgenomic phenotype of end-stage lamin heart disease. Methods: Consecutive patients with end-stage lamin heart disease (LMNA-group, n=7) and ischaemic DCM (ICM-group, n=7) undergoing heart transplantation were enrolled. Samples were obtained from left atrium(LA), left ventricle(LV), right atrium(RA), right ventricle(RV) and interventricular septum(IVS). Liquid chromatography combined with mass-spectrometry was used for protein quantification. We compared protein concentrations in cardiac samples between LMNA and ICM groups. Proteins were considered differentially abundant if the quantitative difference was 1.5-fold and corrected p-value <0.05 at a false discovery rate of 0.01. Gene ontology(GO) enrichment analysis explored the related biological processes. Results: 4,247 proteins were identified in LMNA and ICM samples, of which 633 were differentially abundant in LA, 39 in LV, 181 in RA, 52 in RV, and 85 in IVS. Abundance of lamin A/C was reduced but lamin B (LMNB) increased in LMNA LA/RA tissue compared to ICM, but not in LV/RV. Transthyretin was more abundant in the LV/RV of LMNA compared to ICM while sarcomeric proteins such as titin and cardiac myosin heavy chain were generally reduced in RA/LA of LMNA. Protein expression profiling and GO enrichment analysis revealed sarcopenia, extracellular matrix(ECM) remodeling, deficient myocardial energetics, redox imbalances, and abnormal calcium handling in LMNA samples. Conclusion: Lamin heart disease is a biventricular and biatrial disease, characterized by sarcopenia, aberrant metabolism, and ECM remodeling. LMNB and transthyretin were unexpectedly abundant in the atria and ventricles respectively of patients with end-stage lamin heart disease potentially hinting to the possibility of compensatory responses.
2024-01-26 | PXD040488 | Pride
Project description:Mutations in LMNA, encoding Lamin A/C, lead to a variety of diseases known as laminopathies that include dilated cardiomyopathy (DCM). The role of epigenetic mechanisms. such as DNA methylation, has not been thoroughly investigated. Furthermore, the impact of patient-specific LMNA mutations on DNA methylation is unknown. To explore the role of DNA methylation in the context of unique LMNA mutations, we performed reduced representation bisulfite sequencing (RRBS) on ten pairs of fibroblasts and their induced pluripotent stem cell (iPSC) derivatives from two families with DCM due to distinct LMNA mutations. Family-specific differentially methylated regions (DMRs) were identified by comparing the DNA methylation landscape of patient and control samples. Fibroblast DMRs were found to enrich for distal regulatory features and transcriptionally repressed chromatin and to associate with genes related to phenotypes found in laminopathies. These DMRs, in combination with transcriptome-wide expression data and Lamina-associated domain (LAD) organization, revealed the presence of inter-family epimutation hotspots near differentially expressed genes, most of which were located near redistributed LADs. Comparison of DMRs found in fibroblasts and iPSCs identified regions where epimutations were persistent across both cell types. Finally, a network of disease-associated genes dysregulated in LMNA mutated cells was uncovered, potentially due to aberrant methylation changes. In conclusion, the use of in vitro culture models of patient-derived cells and differential methylation analysis enabled the identification of epimutation hotspots and dysregulated genes, consistent with a Lamin A/C mutation-specific epigenetic disease mechanism that arose in somatic and early-developmental cell stages.
2021-07-20 | GSE164365 | GEO
Project description:Lamin A/C proteins, encoded by the LMNA gene, are intermediate filament proteins of the nuclear lamina, and predominantly expressed in differentiated cells including cardiomyocytes. Mutations in LMNA are associated with laminopathies, congenital diseases affecting muscle and homeostasis. One of the laminopathies associated with a missense mutation (N195K) in the A-type lamins results in dilated cardiomyopathy (DCM) with arrhythmias and sudden death. However it is unknown how the mutation in this LMNA gene contributes to the mechanism of arrhythmia and sudden death. To investigate this a mouse line expressing the Lmna-N195K (LmnaN195K/N195K) was used. Mutant mice demonstrated reduced fractional shortening, LV mass, wall thickness and dilated cardiomyopathy by echocardiography at 6 weeks consistent with human DCM, and died at an early age (6-7 weeks). Comparative cDNA microarray analysis from LmnaN195K/N195K and the wild type (WT) control ventricles at 6 weeks age revealed significant alterations in the expression of ion channels, transporter proteins, caveolins and associated proteins such as MAP kinases. Transmission electron microscopy analysis showed structural alterations of the ventricular myocytes with increase in number of caveolae. Quantitative Western blot analysis confirmed reduced expression for Cavβ (2 fold) subunits of the L-type Ca2+ channel. In contrast the expression levels of Cav3 (2.5 fold) was significantly increased. To investigate the functional impact of Lmna N195K on the ICa,L, we transiently expressed either the WT LMNA+GFP, Lmna N195K+GFP or GFP (control) in isolated neonatal mouse ventricular myocytes and performed whole cell patch clamp analysis. Transient expression of Lmna N195K significantly reduced (58 %) peak ICa,L (-6.0 ± 2 pA/pF, n=9) compared to GFP control (-14 ± 2 pA/pF, n=8). Expression of WT LMNA did not affect the ICa,L (-14.2 ± 2.5 pA/pF, n=8) compared to control. Conclusion: We conclude that Lmna N195K mutation results in reduced expression of ion channels and scaffolding proteins in the left ventricle with a significant reduction in peak ICa,L in ventricular myocytes and these may contribute to the mechanism of arrhythmia and dilated cardiomyopathy.
2012-06-01 | GSE36502 | GEO
Project description:Cardiac fibroblasts (CFs) are the primary cells tasked with extracellar matrix reorganization and significantly associated with heart failure (HF). Previous studies have shown that TEAD1 deficiency deteriorated heart development and homeostasis. However, the role of TEAD1 in fibroblasts during cardiac remodeling was still undiscovered. Our study demonstrated that TEAD1 was upregulated predominently in cardiac fibroblasts in mice 4 weeks after transverse aortic constriction (TAC) and Ang-II infusion. Echocardiographic and histological analyses demonstrated that CFs- and myofibroblasts-specific TEAD1 deficiency ameliorated TAC-induced cardiac remodeling and treatment with TEAD1 inhibitor, VT103, mimiced this phenotypic effect. Mechanistically, RNA-seq analysis , ChIP-Seq analysis identified TEAD1 promotes the fibroblast-to-myofibroblast transition through the Wnt signalling pathway. In conclusion, TEAD1 is an essential regulator of the pro-fibrotic CFs phenotype associated with pathological cardiac remodeling via the BRD4/Wnt4 signalling pathway.
2024-01-15 | GSE253118 | GEO
Project description:Mutations in Lamin A/C (LMNA) cause a heterogeneous group of genetic disorders named as laminopathies. LMNA, an inner nuclear membrane protein, is implicated in nuclear genome organization and gene expression. Our objectives were to identify and define the coding and noncoding gene regulatory networks that are controlled by LMNA in the heart. Sequencing of cardiac transcripts from 2-week old wild-type (WT, N=9) and Lmna-/- (N=8) mice showed differential expression of 2,193 protein coding (817 up/1,222 down) and 629 long non-coding RNAs (lncRNAs) (193 up/436 down,) in Lmna-/- as compared to WT hearts. AAV9 mediated re-introduction of WT LMNA in the Lmna-/- mouse heart was associated with expression changes of (normalization towards WT) of transcript levels of 1,862 coding genes and 607 lncRNAs. Of these 500 coding and 208 lncRNAs showed complete rescue in expression upon LMNA reintroduction. Restoration of the transcript levels was associated with improved heart function and increased survival. Analysis of rescued genes identified histone H3K4 demethylases KDM5A and KDM5B, among the most activated transcriptional regulators. GO analysis for KDM5A targets showed enrichment of genes involved in mitochondrial function and oxidative phosphorylation whereas KDM5B targets were enriched for those involved in cell proliferation and differentiation. Furthermore, based on the publicly available KDM5A ChIP-seq, 124 differentially expressed lncRNAs were identified as putative targets of KDM5A. Consistent with these findings KDM5A and 5B protein levels is increased in nuclear extracts from Lmna-/- heart and are partially rescued upon AAV9 treatment. Thus, the findings implicate dysregulation of KDM5 and its downstream regulatory network involved in the pathogenesis of laminopathies.
2020-11-18 | GSE135288 | 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