Hypoxia-responsive ZEB2 regulates a network of calcium handling genes in the injured heart
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ABSTRACT:
PROVIDER: PRJNA992493 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25194854.fastq.gz | Fastqsanger.gz | |||
| SRR25194854_1.fastq.gz | Fastqsanger.gz | |||
| SRR25194854_2.fastq.gz | Fastqsanger.gz | |||
| SRR25194855.fastq.gz | Fastqsanger.gz | |||
| SRR25194855_1.fastq.gz | Fastqsanger.gz |
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Project description:Intracellular calcium (Ca2+) overload is known to play a critical role in the development of cardiac dysfunction. Despite the remarkable improvement in managing the progression of heart disease, developing effective therapies for heart failure (HF) remains a challenge. A better understanding of molecular mechanisms that maintain proper Ca2+ levels and contractility in the injured heart could be of therapeutic value. Here, we report that the transcription factor Zinc finger E-box-binding homeobox2 (ZEB2) is induced by Hypoxia-inducible factor 1-alpha (HIF1a) in hypoxic cardiomyocytes and regulates a network of genes involved in Ca2+-handling and contractility during ischemic heart disease. Gain- and loss-of-function studies in genetic mouse models revealed ZEB2 in cardiomyocytes to be necessary and sufficient to protect the heart against ischemia-induced diastolic dysfunction and structural remodeling. Moreover, RNA sequencing (RNA-seq) of ZEB2-overexpressing (Zeb2 cTg) hearts post-injury implicated ZEB2 in regulating numerous Ca2+-handling and contractility-related genes. Mechanistically, ZEB2 overexpression increased the phosphorylation of phospholamban (PLN) at both serine-16 and threonine-17, implying enhanced activity of sarcoplasmic reticulum Ca2+-ATPase (SERCA2a), thereby augmenting SR Ca2+ uptake and contractility. Furthermore, we observed a decrease in the activity of Ca2+-dependent calcineurin/NFAT signaling in Zeb2 cTg hearts, which is the main driver of pathological cardiac remodeling. On a post-transcriptional level, we showed that ZEB2 expression can be regulated by the cardiomyocyte-specific microRNA-208a (miR-208a). Blocking the function of miR-208a with antimiR-208a increased ZEB2 expression in the heart and effectively protected from the development of pathological cardiac hypertrophy. Together, we present ZEB2 as a central regulator of contractility and Ca2+-handling components in the mammalian heart. Further mechanistic understanding of the role of ZEB2 in regulating Ca2+ homeostasis in cardiomyocytes is an essential step towards the development of improved therapies for HF.
2024-12-19 | GSE236827 | GEO
Project description:AimsIntracellular calcium (Ca2+) overload is known to play a critical role in the development of cardiac dysfunction. Despite the remarkable improvement in managing the progression of heart disease, developing effective therapies for heart failure (HF) remains a challenge. A better understanding of molecular mechanisms that maintain proper Ca2+ levels and contractility in the injured heart could be of therapeutic value.Methods and resultsHere, we report that transcription factor zinc finger E-box-binding homeobox 2 (ZEB2) is induced by hypoxia-inducible factor 1-alpha (HIF1α) in hypoxic cardiomyocytes and regulates a network of genes involved in Ca2+ handling and contractility during ischaemic heart disease. Gain- and loss-of-function studies in genetic mouse models revealed that ZEB2 expression in cardiomyocytes is necessary and sufficient to protect the heart against ischaemia-induced diastolic dysfunction and structural remodelling. Moreover, RNA sequencing of ZEB2-overexpressing (Zeb2 cTg) hearts post-injury implicated ZEB2 in regulating numerous Ca2+-handling and contractility-related genes. Mechanistically, ZEB2 overexpression increased the phosphorylation of phospholamban at both serine-16 and threonine-17, implying enhanced activity of sarcoplasmic reticulum Ca2+-ATPase (SERCA2a), thereby augmenting SR Ca2+ uptake and contractility. Furthermore, we observed a decrease in the activity of Ca2+-dependent calcineurin/NFAT signalling in Zeb2 cTg hearts, which is the main driver of pathological cardiac remodelling. On a post-transcriptional level, we showed that ZEB2 expression can be regulated by the cardiomyocyte-specific microRNA-208a (miR-208a). Blocking the function of miR-208a with anti-miR-208a increased ZEB2 expression in the heart and effectively protected from the development of pathological cardiac hypertrophy.ConclusionTogether, we present ZEB2 as a central regulator of contractility and Ca2+-handling components in the mammalian heart. Further mechanistic understanding of the role of ZEB2 in regulating Ca2+ homeostasis in cardiomyocytes is an essential step towards the development of improved therapies for HF.
| S-EPMC11630050 | biostudies-literature
Project description:infarct size and subsequent deterioration in function. The identification of factors that enhance cardiac repair by the restoration of the vascular network is, therefore, of great significance. Here, we show that the transcription factor Zinc finger E-box-binding homeobox 2 (ZEB2) is increased in stressed cardiomyocytes and induces a cardioprotective cross-talk between cardiomyocytes and endothelial cells to enhance angiogenesis after ischemia. Single-cell sequencing indicates ZEB2 to be enriched in injured cardiomyocytes. Cardiomyocyte-specific deletion of ZEB2 results in impaired cardiac contractility and infarct healing post-myocardial infarction (post-MI), while cardiomyocyte-specific ZEB2 overexpression improves cardiomyocyte survival and cardiac function. We identified Thymosin 4 (TMSB4) and Prothymosin (PTMA) as main paracrine factors released from cardiomyocytes to stimulate angiogenesis by enhancing endothelial cell migration, and whose regulation is validated in our in vivo models. Therapeutic delivery of ZEB2 to cardiomyocytes in the infarcted heart induces the expression of TMSB4 and PTMA, which enhances angiogenesis and prevents cardiac dysfunction. These findings reveal ZEB2 as a beneficial factor during ischemic injury, which may hold promise for the identification of new therapies.
2021-03-23 | PXD022212 | Pride
Project description:End-stage heart failure caused by myocardial injury is a leading cause of death in the developed world, with high prevalence and poor prognosis. Current therapies focus on attenuating cardiac remodeling after a cardiovascular event such as myocardial infarction or pressure overload, but no therapy is currently available to halt or reverse disease progression. Recent studies have suggested a cardioprotective function of the Wnt5a inhibitor secreted frizzled-related protein 5 (SFRP5) in preventing adverse cardiac remodeling. However, until now, the underlying molecular mechanisms of SFRP5 treatment in the human heart are not well understood. In this study, we investigated the mechanistic and functional consequences of SFRP5 by establishing knockout and overexpression models in human iPSC-derived cardiomyocytes. Transcriptome profiling and deep pathway analysis revealed an involvement of SFRP5 in the regulation of calcium handling, cardiac contraction, and apoptosis. Functional analysis of iPSC-cardiomyocytes by live-cell calcium imaging confirmed the regulatory role of SFRP5 on calcium homeostasis. Our study uncovered a novel role of SFRP5 as a modulator of calcium handling, providing a deeper molecular understanding of the cardioprotective role of SFRP5 in the human heart.
2023-08-04 | GSE240053 | GEO
Project description:Background - Schizophrenia (SCZ) is a debilitating psychiatric disorder with a large genetic contribution; however, its neurodevelopmental substrates remain largely unknown. Modeling pathogenic processes in SCZ using human iPSC-derived neurons (iNs) has emerged as a promising strategy. Copy number variations (CNV) confer high genetic risk for SCZ, with duplication of the 16p11.2 locus increasing risk 14.5 fold. Methods - To dissect the contribution of excitatory (iENs) versus GABAergic (iGNs) neurons to SCZ pathophysiology, we induced iNs from CRISPR-Cas9 engineered isogenic and SCZ patient-derived iPSCs, and analyzed SCZ-related phenotypes in iEN monocultures and iEN/iGN cocultures. Results - In iEN/iGN cocultures, we found reduced neuronal network firing rate and synchrony at later, but not earlier, stages of in vitro development. These were fully recapitulated in iEN monocultures, indicating a primary role for excitatory neurons. Transcriptomic analysis of isogenic 16p11.2 duplication (DUP) iENs revealed pathway dysregulation related to neuroarchitecture and calcium ion binding. Consistent with this, isogenic DUP iENs showed reduced dendrite length and calcium imaging revealed deficits in calcium handling. Analysis of iENs from 16p11.2 duplication-carrying SCZ patients (SCZ) revealed overlapping deficits in network synchrony, dendrite arborization and calcium handling. Conclusions - Our results indicate 16p11.2 duplication-dependent alterations to SCZ neurodevelopment. Calcium ion binding was the only altered transcriptomic gene set shared between isogenic and patient-derived iENs, suggesting a central role of calcium signaling in 16p11.2 duplication-mediated pathogenesis. Moreover, excitatory dysfunction during early neurodevelopment is implicated as the basis of SCZ pathogenesis in 16p11.2 duplication carriers and supports network synchrony and calcium handling as outcomes directly linked to this genetic mutation.
2022-10-13 | GSE215183 | GEO
Project description:Congenital hydrocephalus (CH), occurring in approximately 1/1000 live births, represents an important clinical challenge due to the limited knowledge of underlying molecular mechanisms. The discovery of novel CH-genes is thus essential to shed light on the intricate processes responsible for ventricular dilatation in CH Here we identify FLVCR1 (Feline Leukemia Virus Subgroup C Receptor 1) as a novel gene responsible for a severe form of CH in humans and mice. Mechanistically, our data reveal that the heme exporter FLVCR1a interacts with IP3R3-VDAC, a complex located on mitochondrial-associated membranes (MAMs) that controls mitochondrial calcium handling. Loss of Flvcr1 in mouse neural stem cells (NSCs) affects mitochondrial calcium levels and energy metabolism, leading to defective cortical neurogenesis and brain ventricle enlargement. These data point to defective NSC calcium handling and metabolic activity as one of the pathogenetic mechanisms driving CH.
2024-08-09 | PXD047897 | Pride
Project description:Secreted-frizzled-related protein 5 modulates calcium handling in human iPSC-cardiomyocytes
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Project description:Extracellular calcium export by the breast ductal epithelium is crucial during lactation and plays a significant role in breast cancer progression. Intraductal calcium deposition is a hallmark of aggressive premalignant lesions. This study tested the hypothesis that microbiome-derived extracellular vesicles (EVs) influence calcium modulation within premalignant breast cancer lesions. Based on the analysis of plasma, serum, saliva, and tissue collected from breast cancer patients and controls (N=150), Lactobacillus rhamnosus (Lr) was chosen as the model microbiota. In a BT-474 human breast cancer cell line monolayer culture under acute calcium stress, Lr EVs enhanced intracellular calcium intake. In a BT474 3D spheroid model under chronic calcium stress, Lr EVs increased extracellular calcium deposition and the mRNA expression of calcium export channel calcium pump isoform 2 (PMCA2) and stromal interaction molecule 1 (STIM1) in a dose-dependent manner. We propose that Lr EVs influence calcium regulation and mineral deposition, thereby affecting premalignant breast cancer progression.
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Project description:Study of loss of ZEB2 in breast cancer cells in vitro and in vivo: gene expression and phenotypic switch to more benign behavior of the cancer cells. Morphological, functional and gene microarray analysis following ZEB2 knockdown in MDAMB231 cells reveals gain of epithelial differentiation, reduction of migration, invasion and metastatic capability. The measurement of ZEB2 transcriptional activity in tumor cells efficiently predicts the probability of breast cancer patient survival. Global gene expression profiles were measured using Affymetrix U133 plus2 microarrays in MDAMB231 cells (control and ZEB2 shRNA and siRNA knockdown cells on plastic)
2016-03-15 | E-GEOD-27966 | biostudies-arrayexpress