Cardiomyocyte-specific ADGRF5 mediates cardiac homeostasis via Gαq coupling
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA856709 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR20028138_1.fastq.gz | Fastqsanger.gz | |||
| SRR20028138_2.fastq.gz | Fastqsanger.gz | |||
| SRR20028139_1.fastq.gz | Fastqsanger.gz | |||
| SRR20028139_2.fastq.gz | Fastqsanger.gz | |||
| SRR20028140_1.fastq.gz | Fastqsanger.gz |
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Project description:G-Protein Coupled Receptors (GPCRs) represent one of the most targeted drug classes in the human genome, accounting for greater than 40% of all FDA-approved drugs, including gold-standard heart failure (HF) therapeutics. However, the second-largest family of GPCRs, known as Adhesion GPCRs (aGPCR), have yet to serve as a clinical target despite increasing evidence of their pathophysiological contributions, representing an area of highly unexplored druggable potential. We identified an aGPCR, known as ADGRF5, to be highly expressed in the left ventricle (LV) of C57BL/6, which we also found increases in response to transaortic constriction (TAC) surgery. To determine the impact of ADGRF5 on cardiac parameters normally or during HF, we generated constitutive cardiomyocyte-specific (αMHC-Cre-driven) ADGRF5 knockout mice (CM-ADGRF5-KO), which displayed normal cardiac structure and function at 12 weeks of age, as assessed via echocardiography, gravimetrics and immunohistochemistry. However, over time CM-ADGRF5-KO mice developed worsened cardiac function and remodeling with increased mortality, even in the absence of pathologic insult, suggesting ADGRF5 provides a homeostatic regulatory function in the heart. We assessed changes in cardiac gene expression at 12 weeks of age, a timepoint prior to the onset of the eccentric remodeling on the CM-ADGRF5-KO mice. We identified 58 differentially expressed genes, with 31 downregulated and 27 upregulated.
2024-07-01 | GSE207703 | GEO
Project description:Adult-onset diseases can be associated with in utero events, but mechanisms for such temporally distant dysregulation of organ function remain unknown. The polycomb histone methyltransferase, Ezh2, stabilizes transcription by depositing repressive histone marks during development that persist into adulthood, but the function of Ezh2-mediated transcriptional stability in postnatal organ homeostasis is not understood. Here, we show that Ezh2 stabilizes the postnatal cardiac gene expression program and prevents cardiac pathology, primarily by repressing the homeodomain transcription factor Six1 in differentiating cardiac progenitors. Loss of Ezh2 in embryonic cardiac progenitors, but not in differentiated cardiomyocytes, resulted in postnatal cardiac pathology, including cardiomyocyte hypertrophy and fibrosis. Loss of Ezh2 caused broad derepression of skeletal muscle genes, including the homeodomain transcription factor Six1, which is expressed in cardiac progenitors but is normally silenced upon cardiac differentiation. Many of the deregulated genes are direct Six1 targets, implying a critical requirement for stable repression of Six1 in cardiac myocytes. Indeed, upon de-repression, Six1 promotes cardiac pathology, as it was sufficient to induce cardiac hypertrophy. Furthermore, genetic reduction of Six1 levels almost completely rescued the pathology of Ezh2-deficient hearts. Thus, repression of a single transcription factor in cardiac progenitors by Ezh2 is essential for stability of the adult heart gene expression program and homeostasis. Our results suggest that epigenetic dysregulation during discrete developmental windows can predispose to adult disease and dysregulated stress responses. Global gene expression profiles of Ezh2-deficient hearts. The right ventricle and the interventricular septum of five wild type (Ezh2f/f) and four Ezh2-deficient (Ezh2f/f;Mef2cAHF::Cre) mice were analyzed.
2011-12-31 | E-GEOD-30076 | biostudies-arrayexpress
Project description:The study of cardiac physiology and disease is hindered by physiological differences between humans and small-animal models. Here, we report the generation of multi-chambered vascularized human cardiac organoids under anisotropic stress, and their applicability to study electro-metabolic coupling in cardiac tissue. The organoids are derived from human induced pluripotent stem cells, and integrate sensors for the simultaneous measurement of oxygen uptake, extracellular field potentials and cardiac contraction at resolutions higher than 10 Hz. The microphysiological system allowed us to find that 1-Hz cardiac respiratory cycles are coupled with electrical activity rather than with mechanical activity, that calcium oscillations drive a mitochondrial respiration cycle, that the pharmaceutical or genetic inhibition of electro-mitochondrial coupling results in arrhythmogenic behaviour, and that the induction of arrythmia by the chemotherapeutic mitoxantrone can be partially reversed by the co-administration of metformin. Microphysiological cardiac systems may further facilitate the study of the mitochondrial dynamics of cardiac rhythms and advance the understanding of cardiac physiology.
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Project description:AP-1 activation mediates postnatal cardiomyocyte maturation
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Project description:Some cell type-specific gene expression is maintained in the maturation of cardiomyocytes, where DNA hypomethylation of gene body regions of a set of specific genes. We used microarrays to detail the global gene expression program underlying the maintenance of cardiomyocyte function and maturation and compared it with DNA methylation status. Cardiomyocytes and cardiac fibroblasts were carefully isolated from neonatal and adult hearts and used fresh for the analysis.
2012-07-05 | E-GEOD-39039 | biostudies-arrayexpress
Project description:Background: Modulation of mRNA splicing acts as an important layer of gene regulation, in addition to transcriptional regulation and epigenetic modifications. RNA binding proteins (RBPs) play essential roles in mediating RNA splicing and are key regulators of heart development and function. Our previous studies demonstrated that RBPMS (RNA-binding protein with multiple splicing) regulates cardiac development through modulating mRNA splicing during embryogenesis. Here we explored the postnatal function of RBPMS in the heart. Methods: We ablated Rbpms in the heart by generating a cardiac-specific knockout mouse line (Myh6-Cre, Rbpmsfl/fl), and evaluated its cardiac functions by histology, echocardiography, and gene expression. Paired-end RNA sequencing and RT-PCR were performed to identify and validate splicing targets of RBPMS in adult mouse hearts. Proximity-dependent Biotin Identification (BioID) assay and mass spectrometry analysis were performed to identify RBPMS binding partners. We also measured contractility and calcium fluxes in isolated mouse cardiomyocytes, and contractile forces of cardiac papillary muscle. Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) were also used as a model to explore the influence of RBPMS on contractility of human cardiomyocytes. Results: he absence of Rbpms in the heart led to dilated cardiomyopathy (DCM) and heart failure, causing early death in mice. Mice with cardiac-specific knockout of Rbpms showed myocardium noncompaction with reduced cardiomyocyte number at the neonatal stage and developed DCM with pervasive myocardial fibrosis in adulthood. We found that RBPMS mediates a largely distinct RNA splicing profile in adult mouse hearts compared to neonatal hearts, indicating a stage-specific modulation of alternative RNA splicing by RBPMS. In adult hearts, RBPMS mainly influenced alternative splicing of genes associated with sarcomere structures and cardiomyocyte contraction, such as Ttn, Pdlim5 and Nexn, to generate new protein isoforms. In neonatal hearts, RBPMS influenced the splicing of cytoskeletal genes. RBMPS was associated with spliceosome factors and other RNA binding proteins that play important roles in the heart, such as RBM20 and GATA4. Importantly, we found that the absence of Rbpms caused severe cardiomyocyte contractile defects and reduced calcium sensitivity in both mouse and hiPSC-CMs. Our results demonstrated that Rbpms is crucial for postnatal cardiac function and cardiomyocyte contractility by regulating RNA alternative splicing. Conclusions: Loss of Rbpms in the heart causes reduced cardiomyocyte number and impaired cardiomyocyte contraction, leading to DCM and heart failure.
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Project description:Cardiomyocyte Transcriptomes in Cardiac Development and Hypertrophy
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Project description:Mammalian hearts had the capability to regenerate cardiomyocyte and completely recover after heart injury within a limited time window after birth. It has been shown that sphingosine 1-phospahte receptor 1 (S1pr1) was highly expressed in cardiomyocytes and played an important role in heart development and pathological cardiac remodeling. Herein, we aim to investigate the role of CM-S1pr1 for cardiac regeneration and tissue repair after heart injury. We generated cardiomyocyte (CM)-specific S1pr1 knock-out mice and showed that CM-specific S1pr1 loss-of-function significantly severely reduced cardiomyocyte proliferation and heart regeneration in neonatal mice after both apex resection and myocardial infarction, whereas S1pr1 gain-of-function by AAV9-mediated CM-specific overexpression of S1pr1 significantly boosted cardiac regeneration and improved cardiac functions after heart injuries. We next identified that S1pr1 activated AKT/mTOR/CyclinD1 and Bcl-2 signaling pathways, and thus promoted cardiomyocyte proliferation and inhibited CM apoptosis, respectively.Of note, we applied CM-targeted gene therapy by AAV9-cTNT to specifically overexpress S1pr1 in cardiomyocytes and achieved an efficient S1pr1 overexpression in CMs in vivo. This CM-targeted strategy to overexpress S1pr1 significantly enhanced cardiac regeneration and improved cardiac functions after myocardial infarction in an adult mouse model, suggesting a potential strategy to boost adult cardiac regeneration in vivo.
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Project description:DEAD box 17 (DDX17) is a typical member of the DEAD box family with transcriptional cofactor activity. Although DDX17 is abundantly expressed in the myocardium, its role in the heart is not fully understood. We generated cardiomyocyte-specific Ddx17-knockout mice and cardiomyocyte-specific Ddx17 transgenic mice and explored the function of DDX17 using various cardiomyocyte injury and heart failure (HF) models. We also validated the correlation between DDX17 expression and cardiac function in myocardial biopsy samples from HF patients. DDX17 was downregulated in myocardial samples from HF mouse models and cardiomyocyte injury models. We found that the cardiomyocyte-specific knockout of DDX17 promotes autophagic flux blockage and cardiomyocyte apoptosis in pathological conditions, resulting in progressive heart dysfunction, thereby leading to maladaptive remodeling and progression of HF. The replenishment of DDX17 in cardiomyocytes protected heart function in pathological conditions. Further studies showed that DDX17 can bind to the transcriptional repressor BCL6 and inhibit the expression of the mitochondrial fission protein DRP1. When DDX17 expression was decreased, the transcriptional repression of BCL6 was reduced, resulting in increased DRP1 expression and mitochondrial fission, which caused autophagy flux blockage and apoptosis in cardiomyocytes, leading to impaired mitochondrial homeostasis and HF. We also verified the clinical correlation of DDX17 expression with cardiac function and DRP1 expression in endomyocardial biopsies from patients with HF. These findings suggest that DDX17 protects cardiac function by promoting mitochondrial homeostasis through the BCL6-DRP1 pathway during HF.
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