Myocardial RNA Sequence Analyses throughout the Course of Mouse Cardiac Laminopathy Identify Differential Expressions of the Key Genes for Cell Cycle Control and Mitochondrial Function
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE133693 | GEO | 2020/04/27
REPOSITORIES: GEO
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Project description:LMNA mutations in patients are responsible for a dilated cardiomyopathy. Molecular mechanisms underlying both the origin and development of the pathology are still unknown. Herein, using mouse pluripotent stem cells (ESC) as well as a mouse model, both harbouring p.H222P Lmna mutation, we found early defects in cardiac differentiation of mutated ESCs and dilatation of mutated embryonic hearts at E13.5 pointing to a developmental origin of the disease. Using mouse ESC, we demonstrate that cardiac differentiation of LmnaH222P/+ was impaired at the mesodermal stage. Expression of Mesp1, a mesodermal cardiogenic gene involved in epithelial-mesenchymal transition (EMT) of epiblast cells as well as Snai1 and Twist, was decreased in LmnaH222P/+ cells when compared to wild type in the course of differentiation. In turn, cardiomyocyte differentiation was impaired. Chromatin immunoprecipitation assay of H3K4me1 in differentiating cells revealed a specific decrease of this histone mark on regulatory regions of Mesp1 and Twist in LmnaH222P/+ cells. Downregulation or inhibition of LSD1 that specifically demethylates H3K4me1 rescued the epigenetic landscape of mesodermal LmnaH222P/+ cells and in turn contraction of cardiomyocytes. Inhibition of LSD1 in pregnant mice or neonatal mice prevented cardiomyopathy in E13.5 LmnaH222P/H222P offsprings and adults, respectively. Thus LSD1 turns out to be a therapeutic target to prevent or cure dilated cardiomyopathy associated laminopathy.
2020-12-21 | GSE156975 | GEO
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 | GSE241587 | GEO
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
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 | GSE241589 | 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: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: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:Over 180 LMNA gene mutations have been identified in human diseases including cardiac and skeletal myopathies, lipodystrophies, and premature aging syndromes. Postulated mechanisms by which these mutations result in different phenotypes include perturbation of normal nuclear structure and chromosome organization, and gene activity. We investigated whether a cardiomyopathic LMNA mutation, E161K, displayed abnormal gene expression. We compared the gene expression profile in the E161K LMNA-mutant heart to that of an end stage LMNA-normal heart. We compared the gene expression levels between two end-stage cardiomyopathic hearts in order to detect the gene expression differences more likely to reflect the LMNA mutation state. A region of left ventricle tissue that was grossly less fibrotic and contained cardiomyocytes of the LMNA-mutant heart was selected for RNA isolation. A region of a male heart that was also end-stage dilated cardiomyopathy, but LMNA-normal and also devoid of obvious fibrosis was selected for RNA isolation. Two technical replicates were performed for each sample, and data were analyzed using two different normalization strategies (Mas5 and RMA).
2010-01-30 | E-GEOD-17476 | biostudies-arrayexpress
Project description: Not available
| S-EPMC7170950 | biostudies-literature
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