Fgf9 promotes adipogenesis and reduces osteogenesis by regulating mesenchymal stromal cells differentiation in adult bone marrow
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ABSTRACT:
PROVIDER: PRJNA1060328 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27401821_1.fastq.gz | Fastqsanger.gz | |||
| SRR27401821_2.fastq.gz | Fastqsanger.gz | |||
| SRR27401822_1.fastq.gz | Fastqsanger.gz | |||
| SRR27401822_2.fastq.gz | Fastqsanger.gz | |||
| SRR27401823_1.fastq.gz | Fastqsanger.gz |
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Project description:In this study, we found that Fgf9 regulates the bone-fat balance by modulating the cell fate determination of BMSCs. Histology and micro-CT analysis demonstrate that Fgf9 S99N mutation (loss-of-function) significantly inhibited the formation of bone marrow adipose tissue (BMAT) in adult mice and alleviated the ovariectomized (OVX) induced bone loss and BMAT accumulation. In vitro cytodifferentiation assays unveiled that the Fgf9 S99N mutation hindered adipogenesis while promoting osteogenesis in BMSCs. Furthermore, recombinant FGF9 stimulation and Fgf9 overexpression in BMSCs demonstrated that Fgf9 significantly promoted adipocyte formation and inhibited osteogenesis in vitro and in vivo. Cytodifferentiation assays at various stages of BMSC differentiation indicated that FGF9 altered the osteogenic and adipogenic potential of BMSCs, particularly during the early stages of differentiation. Transcriptomic and gene expression analyses demonstrated that FGF9 significantly upregulated the expression of adipogenic genes while downregulating osteogenic gene expression at both mRNA and protein levels. KEEG analysis revealed and in vitro differentiation assays with specific inhibitors confirmed that FGF9 modulated bone-fat balance by inhibiting osteogenesis via the MAPK/ERK pathway and promoting adipogenesis by activating the PI3K/AKT and Hippo pathways.
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Project description:3D chromatin organization changes modulate adipogenesis and osteogenesis
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2023-12-14 | GSE249471 | GEO
Project description:We have previously shown that FGF9 is overexpressed in hypoxia through the IRES located in the 5’UTR. To identify the protein that binds to FGF9 IRES and controls FGF9 protein synthesis in hypoxia, FGF9 IRES RNA was in vitro synthesized and used to pulled-down interacting proteins. The RNA-protein complexes were first visualized by sliver staining, followed by cutting specific bands for protein identification using matrix-assisted laser desorption/ionization time-of-flight mass spectrometer (MALDI-TOF MS).
2019-11-13 | PXD012892 | Pride
Project description:Mesenchymal stromal cells (MSCs) can differentiate to various cell types including osteoblasts, chondrocytes, and adipocytes. This cellular flexibility contributes to widespread clinical use of MSCs in tissue repair. However, challenges remain in efficient cellular expansion of MSCs for stem cell therapy. Current MSC culture methods have resulted in reduced self-renewal of MSCs and compromised therapeutic outcomes. This study identifies that nicotinamide mononucleotide (NMN), a key natural NAD+ intermediate, effectively encourages MSC expansion in vitro and in vivo. The in vitro expanded MSCs had heightened osteogenesis, but reduced adipogenesis. Furthermore, NMN supplementation stimulated osteogenesis of endogenous MSCs, and protected bone from aging and irradiation induced damage in mice. Mechanistically, we found that NMN treatment upregulated SIRT1. Genetically overexpressing SIRT1 in MSCs by using Prx1 cre; ColA1flox-stop-flox-SIRT1 mice promoted osteogenesis and reduced adipogenesis in aged mice. Overall, our data demonstrate that NMN promoted MSC self-renewal with strengthened osteogenesis and reduced adipogenesis via upregulating SIRT1 in aged mice.
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Project description:Irx3 controls a sumoylation-dependent epigenetic switch between adipogenesis and osteogenesis
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Project description:Background IRX3 is implicated in genetic predisposition to obesity via the FTO variant locus. IRX3 shows FTO risk allele-dependent upregulation specifically during early adipogenesis, leading to a shift from energy dissipation to fat storage in mature adipocytes. However, how changes in IRX3 expression at one developmental stage affect cellular phenotype at a later stage remains unclear. We here hypothesize that IRX3 regulates adipocyte development via transcriptional modulation of epigenetic reprogramming factors. Methods We combined ChIP-, ATAC- and RNA-sequencing to map direct Irx3 target genes in regions of open chromatin during early adipogenesis of wild-type and Irx3-KO preadipocytes. Gene ontology analyses was performed to identify significantly enriched biological pathways. Denaturing western blotting was used to assess sumoylation levels, and the inhibitor ML-792 was used to specifically block sumoylation. Luciferase assays were performed to estimate effects of ML-792 on Pparγ activity. Bodipy lipid staining, immunofluorescence and qPCR were employed to assess adipogenic differentiation in 3D culture. Alkaline phosphatase and Alizarine Red S staining, as well as immunofluorescence and qPCR were used to assess osteogenic differentiation in 3D culture. Results We identified more than 300 Irx3 binding sites in preadipocytes, and these were almost exclusively restricted to promoter regions, with a strong enrichment of genes related to sumoylation, histone modifications and chromatin remodeling. Genes from every step of the sumoylation cycle were bound by Irx3 and differentially expressed in response to Irx3-KO, leading to increased global sumoylation levels in the KO cells. Irx3 ablation and elevated sumoylation inhibited Pparγ activity and adipogenic differentiation in preadipocytes, both of which could be restored by pharmacological inhibition of sumoylation. The Irx3-KO cells demonstrated reduced epigenetic suppression against osteogenesis, resulting in increased osteogenesis in 3D culture. Finally, osteogenesis induced by Irx3 ablation could partially be reversed by inhibition of sumoylation. Conclusions Our study has uncovered IRX3 as a novel upstream regulator of sumoylation, and a potent controller of epigenetic regulators, both directly and indirectly via suppressing global sumoylation levels. This study indicates that the FTO locus promotes obesity via IRX3-mediated suppression of sumoylation, which promotes adipogenic commitment and differentiation through epigenetic programming.
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Project description:Human mesenchymal stem cells (hMSCs) can be differentiated into adipocytes and osteoblasts. While the transcriptomic and epigenomic changes during adipogenesis and osteogenesis have been characterized, what happens to the chromatin loops is hardly known. Here we induced hMSCs to adipogenic and osteogenic differentiation, and performed 2 kb resolution Hi-C experiments for loop detection and generated RNA-seq, histone modification ChIP-seq and ATAC-seq data for integrative analysis before and after differentiation. We quantitatively identified differential contact loops and unique loops. After integrating with multi-omics data, we demonstrate that strengthened loops after differentiation are associated with gene expression activation. Specially, unique loops are linked with cell fate determination. We also proposed loop-mediated regulatory networks and identified IRS2 and RUNX2 as being activated by cell-specific loops to facilitate adipocytes and osteoblasts commitment, respectively. These results are expected to help better understand the long-range regulation in controlling hMSC differentiation, and provide novel targets for studying adipocytes and osteoblasts determination.
2022-08-22 | GSE151322 | GEO
Project description:Human mesenchymal stem cells (hMSCs) can be differentiated into adipocytes and osteoblasts. While the transcriptomic and epigenomic changes during adipogenesis and osteogenesis have been characterized, what happens to the chromatin loops is hardly known. Here we induced hMSCs to adipogenic and osteogenic differentiation, and performed 2 kb resolution Hi-C experiments for loop detection and generated RNA-seq, histone modification ChIP-seq and ATAC-seq data for integrative analysis before and after differentiation. We quantitatively identified differential contact loops and unique loops. After integrating with multi-omics data, we demonstrate that strengthened loops after differentiation are associated with gene expression activation. Specially, unique loops are linked with cell fate determination. We also proposed loop-mediated regulatory networks and identified IRS2 and RUNX2 as being activated by cell-specific loops to facilitate adipocytes and osteoblasts commitment, respectively. These results are expected to help better understand the long-range regulation in controlling hMSC differentiation, and provide novel targets for studying adipocytes and osteoblasts determination.
2022-08-22 | GSE151311 | GEO
Project description:Human mesenchymal stem cells (hMSCs) can be differentiated into adipocytes and osteoblasts. While the transcriptomic and epigenomic changes during adipogenesis and osteogenesis have been characterized, what happens to the chromatin loops is hardly known. Here we induced hMSCs to adipogenic and osteogenic differentiation, and performed 2 kb resolution Hi-C experiments for loop detection and generated RNA-seq, histone modification ChIP-seq and ATAC-seq data for integrative analysis before and after differentiation. We quantitatively identified differential contact loops and unique loops. After integrating with multi-omics data, we demonstrate that strengthened loops after differentiation are associated with gene expression activation. Specially, unique loops are linked with cell fate determination. We also proposed loop-mediated regulatory networks and identified IRS2 and RUNX2 as being activated by cell-specific loops to facilitate adipocytes and osteoblasts commitment, respectively. These results are expected to help better understand the long-range regulation in controlling hMSC differentiation, and provide novel targets for studying adipocytes and osteoblasts determination.
2022-08-22 | GSE151319 | GEO