EPAS1 induction drives myocardial degeneration in Desmoplakin-cardiomyopathy [TOMO-seq]
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PROVIDER: PRJNA1223853 | ENA |
REPOSITORIES: ENA
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Project description:Arrhythmogenic cardiomyopathy (ACM) is frequently attributed to desmosomal mutations, such as those in the desmoplakin (DSP) gene. Patients with DSP- cardiomyopathy are predisposed to myocardial degeneration and arrhythmias. Despite advancements, the underlying molecular mechanisms remain incompletely understood, thus limiting therapeutic options. Here, we employed spatial transcriptomics on an explanted heart from a patient with a pathogenic DSP variant. Our transcriptional analysis revealed endothelial PAS domain-containing protein 1 (EPAS1) as a potential regulator of mitochondrial homeostasis in stressed cardiomyocytes. Elevated EPAS1 levels were associated with mitochondrial dysfunction and hypoxic stress in both human-relevant in vitro ACM models and additional explanted hearts with genetic cardiomyopathy. Collectively, cardiomyocytes bearing pathogenic DSP variants exhibit mitochondrial dysfunction, increased apoptosis, and impaired contractility, which are linked to the increased EPAS1 levels. These findings implicate EPAS1 as a key regulator of myocardial degeneration in DSP-cardiomyopathy, which expand to other forms of ACM.
2025-02-15 | GSE289630 | GEO
Project description:Arrhythmogenic cardiomyopathy (ACM) is frequently attributed to desmosomal mutations, such as those in the desmoplakin (DSP) gene. Patients with DSP- cardiomyopathy are predisposed to myocardial degeneration and arrhythmias. Despite advancements, the underlying molecular mechanisms remain incompletely understood, thus limiting therapeutic options. Here, we employed spatial transcriptomics on an explanted heart from a patient with a pathogenic DSP variant. Our transcriptional analysis revealed endothelial PAS domain-containing protein 1 (EPAS1) as a potential regulator of mitochondrial homeostasis in stressed cardiomyocytes. Elevated EPAS1 levels were associated with mitochondrial dysfunction and hypoxic stress in both human-relevant in vitro ACM models and additional explanted hearts with genetic cardiomyopathy. Collectively, cardiomyocytes bearing pathogenic DSP variants exhibit mitochondrial dysfunction, increased apoptosis, and impaired contractility, which are linked to the increased EPAS1 levels. These findings implicate EPAS1 as a key regulator of myocardial degeneration in DSP-cardiomyopathy, which expand to other forms of ACM.
2025-02-15 | GSE289628 | GEO
Project description:EPAS1 induction drives myocardial degeneration in Desmoplakin-cardiomyopathy [RNA-seq]
| PRJNA1223854 | ENA
Project description:Patients diagnosed with arrhythmogenic cardiomyopathy (ACM) often harbor desmosomal mutations, predisposing them to arrhythmia and sudden cardiac death. The molecular mechanisms underlying pathobiology remain incompletely understood, which is reflected by the limited number of therapeutic strategies. Here, we performed spatially resolved transcriptomics on an explanted heart isolated from a patient bearing a mutation in desmoplakin. Exploration of the transcriptional atlas uncovered endothelial PAS domain-containing protein 1 (EPAS1) as a potential regulator of mitochondrial homeostasis in stressed cardiomyocytes. By combining these data with multiple models of cardiac disease, we show that induced EPAS1 levels activate expression of genes involved in mitophagy and the antioxidant response. Findings were validated in additional explanted heart from ACM and dilated cardiomyopathy patients. Together, genetically impaired cardiomyocytes display mitochondrial dysfunction, consequently resulting in stabilization of EPAS1. In turn, this factor dictates a gene network involved in mitigating the adverse effects of oxidative stress.
2025-09-14 | GSE213539 | GEO
Project description:Patients diagnosed with arrhythmogenic cardiomyopathy (ACM) often harbor desmosomal mutations, predisposing them to arrhythmia and sudden cardiac death. The molecular mechanisms underlying pathobiology remain incompletely understood, which is reflected by the limited number of therapeutic strategies. Here, we performed spatially resolved transcriptomics on an explanted heart isolated from a patient bearing a mutation in desmoplakin. Exploration of the transcriptional atlas uncovered endothelial PAS domain-containing protein 1 (EPAS1) as a potential regulator of mitochondrial homeostasis in stressed cardiomyocytes. By combining these data with multiple models of cardiac disease, we show that induced EPAS1 levels activate expression of genes involved in mitophagy and the antioxidant response. Findings were validated in additional explanted heart from ACM and dilated cardiomyopathy patients. Together, genetically impaired cardiomyocytes display mitochondrial dysfunction, consequently resulting in stabilization of EPAS1. In turn, this factor dictates a gene network involved in mitigating the adverse effects of oxidative stress.
2025-09-14 | GSE213540 | GEO
Project description:Arrhythmogenic cardiomyopathy (ACM) is frequently attributed to desmosomal mutations, such as those in the desmoplakin (DSP) gene. Patients with DSP-cardiomyopathy are predisposed to myocardial degeneration and arrhythmias. Despite advancements, the underlying molecular mechanisms remain incompletely understood, thus limiting therapeutic options. Here, we employed spatial transcriptomics on an explanted heart from a patient with a pathogenic DSP variant. Our transcriptional analysis revealed endothelial PAS domain-containing protein 1 (EPAS1) as a potential regulator of mitochondrial homeostasis in stressed cardiomyocytes. Elevated EPAS1 levels were associated with mitochondrial dysfunction and hypoxic stress in both human-relevant in vitro ACM models and additional explanted hearts with genetic cardiomyopathy. Collectively, cardiomyocytes bearing pathogenic DSP variants exhibit mitochondrial dysfunction, increased apoptosis, and impaired contractility, which are linked to the increased EPAS1 levels. These findings implicate EPAS1 as a key regulator of myocardial degeneration in DSP-cardiomyopathy, which expand to other forms of ACM.
| S-EPMC11872638 | biostudies-literature
Project description:Mutations in desmosome genes cause arrhyythmogenic cardiomyopathy (ACM). Using desmoplakin haploinsufficient mouse model of ACM, we evaluated the effects of treadmill exercise on cardiac myocyte transcritional profile. Strand specific, ribosome depleted paired end RNA sequencing of cardiac myocytes from wild type and Myh6-Cre:DspW/F were generate using Illumina HiSeq 4000.
2020-04-29 | GSE129962 | GEO
Project description:Aims Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disorder that is characterized by progressive fibro-fatty replacement of the myocardium, arrhythmias, and sudden death. While myocardial degeneration and fibro-fatty replacement occurs in specific locations, the underlying molecular changes remain poorly characterized. Here we aim to delineate local changes in gene expression to help identify new genes or pathways that are relevant for specific remodelling processes occurring during ACM. Methods and Results Using Tomo-Seq, a genome-wide transcriptional profiling with high spatial resolution, we created a transmural epicardial to endocardial gene expression atlas of an explanted ACM heart to gain molecular insights into disease-driving processes. This enabled us to link gene expression profiles to the different regional remodelling responses and allowed us to identify genes that are potentially relevant for disease progression. In doing we revealed BTB (broad-complex, tramtrack, bric-à-brac) domain containing 11 (ZBTB11) to be specifically enriched at sites of active fibrofatty replacement of myocardium. Immunohistochemistry indicated ZBTB11 to be enriched in cardiomyocytes flanking fibrofatty areas, which could be confirmed in multiple cardiomyopathy patients. Forced overexpression of ZBTB11 in iPS-derived cardiomyocytes showed ZBTB11 to function as a potent inducer of cardiomyocyte atrophy. Conclusion By combining spatial transcriptomics with classical histological approaches we identified gene expression changes underlying local remodelling responses in ACM. In doing so we found ZBTB11 to function as a relevant driver of cardiomyocyte atrophy. These data show the power of Tomo-Seq to unveil new molecular mechanisms and indicate ZBTB11 as a potential new target for cardiomyopathy.
2021-05-22 | GSE114770 | GEO
Project description:Purpose: By integrating DNA methylation and gene expression of COPD lung tissues, we identified EPAS1 as a key regulator whose downstream genes significantly overlapped with multiple genes sets associated with COPD disease severity. EPAS1 is distinct in comparison with other key regulators in terms of methylation profiles and downstream target genes. Genes predicted to be regulated by EPAS1 were enriched for biological processes including signaling, cell communications, and system developement. As EPAS1 downstream genes were significantly enriched for hypoxia responsive genes in endothelial cells, we tested EPAS1 function in human and mouse endothelial cells HUVEC and C166. EPAS1 knockdown by siRNA in endothelial cells impacted genes that significantly overlapped with EPAS1 downstream genes in lung tissue including hypoxia responsive genes. Methods: The cell lines of HUVEC (Lonza, MD, USA) and C166 (American Type Culture Collection, VA, USA) were cultured in the appropriate media at 37M-BM-0C with 5% CO2. The cells were transfected with EPAS1 siRNA and non-targeting negative control siRNA (Life Technologies, CA, USA) using Lipofectamine RNAiMAX as recommended transfection protocols by the manufacturer. After the treatments with 5nM SilencerM-BM-. Select siRNA (s4700 for EPAS1, s65525 for Epas1; Life Technologies, USA) for 48 hours, the total RNA was purified with RNeasy Mini Kit (QIAGEN, Germany). The efficiencies of knocked down the EPAS1 expression were assessed by qPCR with 1.4% for HUVEC, 3.2% for C166. Approximately 250 ng of total RNA per sample were used for library construction by the TruSeq RNA Sample Prep Kit (Illumina) and sequenced using the Illumina HiSeq 2500 instrument with 100nt single read setting according to the manufacturer's instructions. Sequence reads were aligned to human genome assembly hg19 and mouse genome assembly mm10, respectively, using Tophat [96]. Total 23,228 human and 22,609 mouse genes were quantified using Cufflinks [96]. siRNA signatures were derived by comparing expression profiles of EPAS1 or Epas1 siRNAs with non-targeting siRNAs at paired t-test p-value cutoff 0.05 with resulting signature sizes of 2,796 and 3,730, and corresponding q-values [97] 0.11 and 0.07 for HUVEC and C166, respectively. Results: When comparing endothelial cells treated with EPAS1 siRNAs and scrambled siRNAs, we identified an EPAS1 siRNA signature consisting of 2796 and 3730 genes in human and mouse endothelial cell lines, respectively, whose expression levels significantly changed (t-test p-value<0.05), including EPAS1 itself (p-value = 0.002 and 0.02) and the EPAS1 downstream target gene VEGFA (p-value = 0.03 and 0.01). The EPAS1 siRNA signatures derived from human and mouse cell lines were highly consistent, with 695 genes in common to both signatures (p-value = 7.2x10-65). Both signatures not only significantly overlapped with EPAS1 downstream genes (p-value = 7.3x10-7 and 1.5x10-12), but also with hypoxia response genes in endothelial cells (FisherM-bM-^@M-^Ys Exact Test p-value = 5.8x10-8 and 1.2x10-12 in the human and mouse signatures, respectively). Moreover, the EPAS1 siRNA signatures consistently overlapped genes associated with the COPD severity phenotypes. These results together validate that EPAS1 causally regulates the downstream target genes we predicted, and that these genes in turn affect COPD development and progression. For each of human and mouse cell lines, 3 siRNA control cells, and 3 siRNA EPAS1 knockdown cells were used and analyzed. To identify EPAS1 signatures, paired t-test was performed between control siRNA and EPAS1 siRNA samples.
2015-01-16 | E-GEOD-62974 | biostudies-arrayexpress
Project description:EPAS1 directs a network of genes implicated in mitochondrial dysfunction in arrhythmogenic cardiomyopathy
| PRJNA881311 | ENA