Identification of PITX2 as a novel factor in arrhythmogenic cardiomyopathy pathogenesis
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PROVIDER: PRJNA858786 | ENA |
REPOSITORIES: ENA
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Project description:Identification of PITX2 as a novel factor in arrhythmogenic cardiomyopathy pathogenesis [KI]
| PRJNA858791 | ENA
Project description:Identification of PITX2 as a novel factor in arrhythmogenic cardiomyopathy pathogenesis [patient line]
| PRJNA858790 | ENA
Project description:In this study, we identified a novel heterozygous variant within DSP (c.3562T>C) in a patient diagnosed with ACM. Using CRISPR/Cas9 we corrected patient-derived human induced pluripotent stem cells (hiPSC) and created a knock-in (KI) hiPSC line with the same mutation. Compared to wildtype cardiomyocytes, we observed a prolonged action potential duration (APD) and reduced expression of desmosomal components, which was paralleled by abnormal levels of essential cardiac ion channels. Strikingly, the transcription factor paired-like homeodomain 2 (PITX2), which acts as a repressor of ion channel-related genes, was induced in these cells. Together, we identified PITX2 as a potential missing link between mutations in DSP and the cardiac conductance abnormalities often seen in these patients.
2023-03-02 | GSE208212 | GEO
Project description:In this study, we identified a novel heterozygous variant within DSP (c.3562T>C) in a patient diagnosed with ACM. Using CRISPR/Cas9 we corrected patient-derived human induced pluripotent stem cells (hiPSC) and created a knock-in (KI) hiPSC line with the same mutation. Compared to wildtype cardiomyocytes, we observed a prolonged action potential duration (APD) and reduced expression of desmosomal components, which was paralleled by abnormal levels of essential cardiac ion channels. Strikingly, the transcription factor paired-like homeodomain 2 (PITX2), which acts as a repressor of ion channel-related genes, was induced in these cells. Together, we identified PITX2 as a potential missing link between mutations in DSP and the cardiac conductance abnormalities often seen in these patients.
2023-03-02 | GSE208213 | GEO
Project description:Arrhythmogenic cardiomyopathy is an inherited entity characterized by irregular cell-cell adhesion, cardiomyocyte death, fibro-fatty replacement of ventricular myocytes, leading to malignant ventricular arrythmias, contractile dysfunction and sudden cardiac death. Pathogenic variants in genes that encode desmosome are the predominant cause of arrhythmogenic cardiomyopathy. Moreover, signalling pathways such as Wnt/ß-catenin and transforming growth factor-β have been involved in the disease progression. However, still little is known about the molecular pathophysiological mechanisms that underlie arrhythmogenic cardiomyopathy pathogenesis. We used mRNA and small RNA sequencing to analyse the transcriptome of health and arrhythmogenic cardiomyopathy autopsied human hearts. Our results showed 697 differentially expressed genes, and eight differentially expressed miRNAs. Functional enrichment revealed mitochondrial respiratory-related pathways, impaired response to oxidative stress, apoptotic signalling pathway, inflammatory response-related and extracellular matrix response pathways. Furthermore, analysis of miRNA-mRNA interactome identified eleven negatively correlated miRNA-target pairs for arrhythmogenic cardiomyopathy. Our finding revealed novel arrhythmogenic cardiomyopathy-related miRNAs with important regulatory function in disease pathogenesis highlighting their value as potential key targets for therapeutic approaches.
2024-09-30 | GSE273295 | GEO
Project description:Novel heart specific long non-coding RNAs contribute to pathogenesis of Arrhythmogenic Cardiomyopathy
| PRJNA420232 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-03-02 | GSE208214 | GEO
Project description:The cWNT pathway has been implicated in the pathogenesis of arrhythmogenic cardiomyopathy (ACM), including in cardiac dysfunction, apoptosis, and fibro-adipogenesis, the latter being the histological hallmark of ACM. The study was designed to determine effects of genetic activation or suppression of cWNT in a mouse model of arrhythmogenic cardiomyopathy. The data show that activation of the cWNT in ACM deleterious whereas it suppression is benefiial.
2022-02-02 | GSE180972 | GEO
Project description:Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy primarily of the right ventricle characterized through fibrofatty replacement of cardiomyocytes. The genetic etiology in ARVC patients is most commonly caused by dominant inheritance and high genetic heterogeneity. Though histological examinations of ARVC affected human myocardium reveals fibrolipomatous replacement, the molecular mechanisms leading to loss of cardiomyocytes are largely unknown. We therefore analyzed the transcriptomes of 6 ARVC specimen derived from heart transplantation candidates and compared our findings to 6 non-failing donor hearts (NF) which could not be transplanted for technical reasons. In addition, we compared our findings to 7 hearts from patients with idiopathic dilated cardiomyopathy. From each heart left (LV) and right ventricular (RV) myocardial samples were analyzed by Affymetrix HG-U133 Plus 2.0 arrays, adding up to six sample groups. Unsupervised cluster analyses of the six sample groups revealed a clear separation of NF and cardiomyopathy samples. However, in contrast to the other samples, unsupervised cluster analyses revealed no distinct expression pattern in LV and RV samples from ARVC-hearts. We further identified differentially expressed transcripts using t-tests and found transcripts separating diseased and NF ventricular myocardium. Of note, in failing myocardium only about 15-16% of the genes are commonly regulated compared to NF samples. In addition both cardiomyopathies are clearly distinct on the transcriptome level. Comparison of the expression patterns between the failing RV and LV using a paired t-test revealed a lack of major differences between LV and RV gene expression in ARVC hearts. Microarrays were used to elucidate the differences between non-failing control hearts and those, suffering from arrhythmogenic right ventricular cardiomyopathy (ARVC).
2011-11-30 | E-GEOD-29819 | biostudies-arrayexpress
Project description:Pitx2 is the homeobox gene located in proximity to the human 4q25 familial atrial fibrillation locus. Pitx2 haploinsufficient mice are prone to pacing induced atrial fibrillation indicating that reduced Pitx2 promotes an arrhythmogenic substrate within the atrium. Here, we inactivated Pitx2 in postnatal heart and discovered that unstressed adult Pitx2 mutant mice had sinus node dysfunction with impaired atrial conduction, an arrhythmia closely associated with atrial fibrillation. A genome-wide search for Pitx2 transcriptional targets using ChIP-sequencing and RNA expression profiling shows that Pitx2 represses target genes encoding cell junction proteins, ion channels, and critical transcriptional regulators many of which have been implicated in human atrial fibrillation by genome wide association studies. Our findings unveil a Pitx2 postnatal arrhythmogenic function, novel Pitx2 target genes relevant to atrial fibrillation, and reveal that Pitx2 stabilizes the intercalated disc in postnatal atrium. Genomic occupancy profiling of transcriptional factor Pitx2 in postnatal heart.
2014-02-01 | E-GEOD-47928 | biostudies-arrayexpress