Ghrelin promotes cardiomyocyte differentiation of adipose tissue-derived mesenchymal stem cells by DDX17-mediated regulation of the SFRP4/Wnt/β-catenin axis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA974357 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24658107_1.fastq.gz | Fastqsanger.gz | |||
| SRR24658107_2.fastq.gz | Fastqsanger.gz | |||
| SRR24658108_1.fastq.gz | Fastqsanger.gz | |||
| SRR24658108_2.fastq.gz | Fastqsanger.gz | |||
| SRR24658109_1.fastq.gz | Fastqsanger.gz |
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Project description:To investigate the genes that regulated by ghrelin in the cardiomyocyte differentiation of ADMSCs, we cultured cells for RNA-Sequencing.
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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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Project description:We utilized single cell sequencing of FACS sorted cells from pancreatic islets of wildtype and ghrelin knock out mice to understand the effects of ghrelin deletion on gene expression profiles of various islet cells.
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Project description:Hepatic fibrosis, the wound-healing response to repeated liver injury, ultimately leads to cirrhosis. There is an urgent need to develop effective antifibrotic therapies. Ghrelin (encoded by Ghrl) is an orexigenic hormone that has pleiotrophic functions including protection against cell death1. Here we investigate whether ghrelin modulates liver fibrosis and protects from acute liver injury. Recombinant ghrelin reduced the fibrogenic response to prolonged bile duct ligation in rats. This effect was associated with decreased liver injury and myofibroblast accumulation as well as attenuation of the altered gene expression profile. Ghrelin also reduced fibrogenic properties in cultured hepatic stellate cells. Moreover, Ghrl-/- mice developed exacerbated hepatic fibrosis and liver damage after chronic injury. Ghrelin also protected rat livers from acute liver injury and reduced the extent of oxidative stress and the inflammatory response. In patients with chronic liver diseases, ghrelin serum levels decreased in those with advanced fibrosis and hepatic expression of the ghrelin gene correlated with expression of fibrogenic genes. Finally, in patients with chronic hepatitis C, single nucleotide polymorphisms of the ghrelin gene (-994CT and â604GA) influenced the progression of liver fibrosis. We conclude that ghrelin exerts antifibrotic effects on the liver and may represent a novel antifibrotic therapy. Experiment Overall Design: Rats were divided into three groups: control rats receiving saline (sham operation), rats with bile duct ligation receiving saline and rats with bile duct ligation receiving recombinant ghrelin (10 micrograms/Kg/day by a subcutaneous osmotic mimi-pump). For the microarray analysis samples from 6 rats were analyzed except for the ghrelin-treated group (5 rats).
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Project description:Ghrelin, an orexigenic gut-derived peptide, is gaining increasing attention due to its multifaceted role in a number of physiological functions, including metabolism, cardiovascular health, stress and reproduction. Ghrelin exists in circulation primarily as des-acylated and acylated ghrelin. Des-acyl ghrelin, until recently considered to be an inactive form ghrelin, is now known to have independent physiological functionality. However, the relative contribution of acyl and des-acyl ghrelin to reproductive development and function is currently unknown. Here we used ghrelin-O-acyltransferase (GOAT) knockout (KO) mice that have no measurable levels of endogenous acyl ghrelin and chronically high levels of des-acyl ghrelin, to characterise how the developmental and life-long absence of acyl ghrelin affects ovarian development and reproductive capacity. We have combined ovarian transcriptome analysis using RNA sequencing with measures of ovarian morphometry, as well as with the assessment of markers of reproductive maturity and the capacity to breed. Our data show pronounced specific changes in the ovarian transcriptome in the juvenile GOAT KO ovary, indicative of advanced ovarian development. These changes corresponded with diminished ovarian reserve in the juvenile and adult ovaries of these mice, due to a continuous reduction in the number of small follicle populations. These changes did not affect the timing of puberty onset or reproductive capacity under optimal conditions. These data suggest that an absence of acyl ghrelin does not prevent reproductive success but that appropriate levels of acyl and des-acyl ghrelin may be necessary for optimal ovarian maturation.
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Project description:Hepatic fibrosis, the wound-healing response to repeated liver injury, ultimately leads to cirrhosis. There is an urgent need to develop effective antifibrotic therapies. Ghrelin (encoded by Ghrl) is an orexigenic hormone that has pleiotrophic functions including protection against cell death1. Here we investigate whether ghrelin modulates liver fibrosis and protects from acute liver injury. Recombinant ghrelin reduced the fibrogenic response to prolonged bile duct ligation in rats. This effect was associated with decreased liver injury and myofibroblast accumulation as well as attenuation of the altered gene expression profile. Ghrelin also reduced fibrogenic properties in cultured hepatic stellate cells. Moreover, Ghrl-/- mice developed exacerbated hepatic fibrosis and liver damage after chronic injury. Ghrelin also protected rat livers from acute liver injury and reduced the extent of oxidative stress and the inflammatory response. In patients with chronic liver diseases, ghrelin serum levels decreased in those with advanced fibrosis and hepatic expression of the ghrelin gene correlated with expression of fibrogenic genes. Finally, in patients with chronic hepatitis C, single nucleotide polymorphisms of the ghrelin gene (-994CT and –604GA) influenced the progression of liver fibrosis. We conclude that ghrelin exerts antifibrotic effects on the liver and may represent a novel antifibrotic therapy.
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Project description:DDX17 is a DEAD-box RNA helicase protein which is involved in many aspects of RNA metabolism, from gene transcription to RNA processing and decay. As a simple approach to identify DDX17 target genes, we carried out a transcriptome analysis of the human neuroblastoma cell line SH-SY5Y following DDX17 gene knock-down
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Project description:Short interspersed element (SINE) RNAs are upregulated by cellular stresses1 (heat shock, DNA damage and viral infection) and accumulate in human diseases (macular degeneration2, lupus3, and Alzheimer’s disease4). These transcripts activate inflammasomes5, a family of cytoplasmic multiprotein complexes that sense danger molecules and initiate innate immune responses by activating caspase-1-dependent cytokine production and inflammatory death6, but the molecular sensor of SINE RNAs is unknown. Here, we identify DDX17, a member of the DEAD box family of RNA helicases7, as a sensor of SINE RNAs requisite for inflammasome activation. Induction of caspase-1 cleavage and release of IL-1 and IL-18 by SINE RNAs requires dual recruitment of NLRP3 and NLRC4 but proceeds independent of NAIPs, immune sensors required for canonical NLRC4 activation by bacterial proteins8,9. Instead, SINE RNAs trigger DDX17–NLRC4 interaction, which licenses inflammasome activation. We also report increased levels of DDX17 protein and association of DDX17 and NLRC4 in the retinal pigmented epithelium (RPE) of human eyes with an advanced, untreatable form of age-related macular degeneration (AMD). Disrupting DDX17–NLRC4 signalling blocks SINE RNA-induced inflammasome activation in human RPE cells and RPE degeneration in an animal model of AMD. Our findings uncover a non-canonical mode of inflammasome activation by endogenous retrotransposon transcripts, and provide new potential targets for macular degeneration and potentially other diseases.
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