The anti-aging protein Klotho affects early postnatal myogenesis by down-regulating Jmjd3 and the canonical Wnt pathway
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA781582 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16975405.fastq.gz | Fastqsanger.gz | |||
| SRR16975406.fastq.gz | Fastqsanger.gz | |||
| SRR16975407.fastq.gz | Fastqsanger.gz | |||
| SRR16975408.fastq.gz | Fastqsanger.gz |
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Project description:Modulating the number of muscle stems cells, called satellite cells, during early postnatal development produces long-term effects on muscle growth. We tested the hypothesis that high expression levels of the anti-aging protein Klotho in early postnatal myogenesis increase satellite cell numbers by influencing the epigenetic regulation of genes that regulate myogenesis. Our findings show that elevated klotho expression caused a transient increase in satellite cell numbers and slowed muscle fiber growth, followed by a period of accelerated muscle growth that resulted in larger fibers. Klotho also transcriptionally down-regulated the H3K27 demethylase Jmjd3, increased H3K27 methylation and decreased expression of genes in the canonical Wnt pathway, which was associated with a significant delay in muscle differentiation. In addition, Klotho stimulation and subsequent Jmjd3 down-regulation produced similar but not additive reductions in the expression of Wnt4, Wnt9a and Wnt10a in myogenic cells, indicating that inhibition occurred through a common pathway. Together, our results identify a novel pathway through which Klotho influences myogenesis by reducing expression of Jmjd3, leading to reductions in the expression of Wnt genes and inhibition of canonical Wnt signaling.
2022-04-20 | GSE189109 | GEO
Project description:Modulating the number of muscle stems cells, called satellite cells, during early postnatal development produces long-term effects on muscle growth. We tested the hypothesis that high expression levels of the anti-aging protein Klotho in early postnatal myogenesis increase satellite cell numbers by influencing the epigenetic regulation of genes that regulate myogenesis. Our findings show that elevated klotho expression caused a transient increase in satellite cell numbers and slowed muscle fiber growth, followed by a period of accelerated muscle growth that leads to larger fibers. Klotho also transcriptionally downregulated the H3K27 demethylase Jmjd3, leading to increased H3K27 methylation and decreased expression of genes in the canonical Wnt pathway, which was associated with a delay in muscle differentiation. In addition, Klotho stimulation and Jmjd3 downregulation produced similar but not additive reductions in the expression of Wnt4, Wnt9a, and Wnt10a in myogenic cells, indicating that inhibition occurred through a common pathway. Together, our results identify a novel pathway through which Klotho influences myogenesis by reducing the expression of Jmjd3, leading to reductions in the expression of Wnt genes and inhibition of canonical Wnt signaling.
| S-EPMC9007106 | biostudies-literature
Project description:Klotho functions as an aging suppressor, which, in mice, extends lifespan when overexpressed and accelerates development of aging-like phenotypes when disrupted. Klotho is mainly expressed in brain and kidney and is secreted into the serum and CSF. We have previously shown that Klotho is reduced in brains of old monkeys, rats and mice. We further reported the ability of Klotho to enhance oligodendrocyte differentiation and myelination. Here we examined the effects of Klotho on MO3.13, a human oligodendroglioma cell line in order to determine the potential role of Klotho as a tumor suppressor. We show that exogenous Klotho affects the ERK and Akt signaling pathways and decreases the proliferative abilities of MO3.13 cells. Furthermore, microarray analysis of Klotho-treated MO3.13 cells reveals a massive change in gene expression with 80% of the differentially expressed genes being downregulated. Using gene set enrichment analysis we predicted potential transcription factors involved in regulating Klotho-treated MO3.13 cells and found that these cells are highly enriched in the gene sets, that are similarly observed in cancer, cardiovascular disease, stress, aging and hormone-related chemical and genetic perturbations. Since Klotho is downregulated in all brain tumors tested to date, enhancing Klotho has therapeutic potential for treating brain malignancies. 6 Samples
2014-06-09 | E-GEOD-51536 | biostudies-arrayexpress
Project description:To assess the transcriptomic response to Klotho deficiency in the renal distal convolution (DC), we isolated DC cells from control and DC-specific Klotho KO mice using COPAS (Complex Object Parametric Analyzer and Sorter). Further comprehensive and unbiased RNA-seq identified altered transcripts associated with canonical MAPK pathway, as well as many novel targets of Klotho.
2023-12-15 | GSE247008 | GEO
Project description:Direct reprogramming of fibroblasts into cardiomyocytes (CMs) represents a promising strategy to regenerate CMs lost after ischemic heart injury. Overexpression of GATA4, HAND2, MEF2C, TBX5, miR-1, and miR-133 (GHMT2m) along with transforming growth factor beta (TGFbeta) inhibition efficiently promotes reprogramming. However, the mechanisms by which TGFbeta; blockade promotes cardiac reprogramming remain unknown. Here, we identify interactions between the histone H3 lysine 27 trimethylation (H3K27me3), demethylase JMJD3, the SWI/SNF remodeling complex subunit BRG1, and cardiac transcription factors. Furthermore, canonical TGFbeta; signaling regulates the interaction between GATA4 and JMJD3. TGF-beta; activation impairs the ability of GATA4 to bind target genes and prevents demethylation of H3K27 at cardiac gene promoters during cardiac reprogramming. Finally, a mutation in GATA4 (V267M) exhibits reduced binding to JMJD3 and impaired cardiomyogenesis. Thus, we have identified an epigenetic mechanism wherein canonical TGFbeta; pathway activation impairs cardiac gene programming by interfering with GATA4-JMJD3 interactions.
2021-02-13 | GSE145290 | GEO
Project description:Klotho functions as an aging suppressor, which, in mice, extends lifespan when overexpressed and accelerates development of aging-like phenotypes when disrupted. Klotho is mainly expressed in brain and kidney and is secreted into the serum and CSF. We have previously shown that Klotho is reduced in brains of old monkeys, rats and mice. We further reported the ability of Klotho to enhance oligodendrocyte differentiation and myelination. Here we examined the effects of Klotho on MO3.13, a human oligodendroglioma cell line in order to determine the potential role of Klotho as a tumor suppressor. We show that exogenous Klotho affects the ERK and Akt signaling pathways and decreases the proliferative abilities of MO3.13 cells. Furthermore, microarray analysis of Klotho-treated MO3.13 cells reveals a massive change in gene expression with 80% of the differentially expressed genes being downregulated. Using gene set enrichment analysis we predicted potential transcription factors involved in regulating Klotho-treated MO3.13 cells and found that these cells are highly enriched in the gene sets, that are similarly observed in cancer, cardiovascular disease, stress, aging and hormone-related chemical and genetic perturbations. Since Klotho is downregulated in all brain tumors tested to date, enhancing Klotho has therapeutic potential for treating brain malignancies.
2014-06-09 | GSE51536 | GEO
Project description:α-Klotho has emerged as a powerful regulator of the ageing process. To-date, the expression profile of α-Klotho in human tissues is unknown and its existence in some human tissue types is subject to much controversy. Objective: This is the first study to characterize system-wide tissue expression of transmembrane α-Klotho in humans. We have employed next generation targeted proteomic analysis using Parallel Reaction Monitoring (PRM) in parallel with conventional antibody-based methods to determine the expression and spatial distribution of human α-Klotho expression in health. Results: The distribution of α-Klotho in human tissues from various organ systems, including arterial, epithelial, endocrine, reproductive and neuronal tissues was first identified by immunohistochemistry. Kidney tissues showed strong α-Klotho expression, while liver did not reveal a detectable signal. These results were next confirmed by western blotting of both whole tissues and primary cells. To validate our antibody-based results, α-Klotho expressing tissues were subjected to PRM mass spectrometry identifying peptides specific for the full length, transmembrane α-Klotho isoform. Conclusions: The data presented confirms α-Klotho expression in the kidney tubule and in artery, and provides evidence of α-Klotho expression across organ systems and cell-types that have not previously been described in humans.
2015-10-13 | PXD002775 | Pride
Project description:Bone-derived hormone FGF23 and its co-receptor Klotho form a trimeric complex with FGFRs in target tissues, thus governing physiological FGF23 actions. Prolonged excess FGF23 levels in conditions like chronic kidney disease (CKD) may have cardiotoxic and inflammatory effects without requiring Klotho as a coreceptor. If and how FGF23 functions independently of Klotho is a topic of significant interest. Using in-vitro transcriptomics and further bioinformatics analysis, here we show that transient-low FGF23 treatment (~physiological) in presence of Klotho exhibit canonical signaling. However lack of Klotho led to almost no change in transcriptomics after FGF23 treatment. On the other hand, prolonged-excess FGF23 treatment (~pathological) revealed many novels targets of FGF23, which are also emerging biomarkers of CKD, suggesting FGF23 may activate these molecules in CKD. Remarkably, Klotho acted as a molecular switch by regulating, together with FGF23, the above-mentioned transcripts, thus determining the fate of FGF23 signaling. Overall, our findings provide proof-of-principle evidence for the Klotho dependent and independent FGF23 actions, which may hold great potential for investigating a precise role of FGF23 in health and disease.
2023-12-06 | GSE248734 | GEO
Project description:We found that a klotho protein fragment (KL-F), administered peripherally, induced cognitive enhancement and neural resilience. Here we report a proteomic analysis of whole hippocampal homogenates from mice treated with vehicle or KL-F (10 µg/kg, i.p.) four hours prior to exploration in the small Y-maze. The proteomic results showed glutamate receptor signaling as the top enriched canonical pathway by Ingenuity Pathway Analysis.
2017-08-09 | PXD007150 | Pride
Project description:Autophagy is essential for cellular survival and energy homeostasis under nutrient deprivation. Despite the emerging importance of nuclear events in autophagy regulation, epigenetic control of autophagy gene transcription remains unclear. Here, we identify Jumonji-D3 (JMJD3/KDM6B) histone demethylase as a key epigenetic activator of hepatic autophagy. Upon fasting-induced fibroblast growth factor-21 (FGF21) signaling, JMJD3 epigenetically upregulated global autophagy-network genes, including Tfeb, Atg7, Atgl, and Fgf21, through demethylation of histone H3K27-me3, resulting in autophagy-mediated lipid degradation. Mechanistically, phosphorylation of JMJD3 at Thr-1044 by FGF21 signal-activated PKA increased its nuclear localization and interaction with the nuclear receptor PPARto transcriptionally activate autophagy. Chronic administration of FGF21 in obese mice improved defective autophagy and hepatosteatosis in a JMJD3-dependent manner. Remarkably, in non-alcoholic fatty liver disease patients, hepatic expression of JMJD3, ATG7, LC3, and KL were substantially decreased. These findings demonstrate that FGF21-JMJD3 signaling epigenetically links nutrient deprivation with hepatic autophagy and lipid degradation in mammals
2020-05-26 | PXD015672 | Pride