FTO SUMOylation regulates the differentiation of bone marrow mesenchymal stromal cells in Inflammatory Bowel Disease-Induced Bone Loss
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ABSTRACT:
PROVIDER: PRJNA1269921 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR33760213_1.fastq.gz | Fastqsanger.gz | |||
| SRR33760213_2.fastq.gz | Fastqsanger.gz | |||
| SRR33760217_1.fastq.gz | Fastqsanger.gz | |||
| SRR33760217_2.fastq.gz | Fastqsanger.gz |
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Project description:Gut-bone axis is critical for body homeostasis, but bone loss often complicates inflammatory bowel disease (IBD) with unclear mechanisms. Here, we found that IBD mice showed reduced bone formation, with bone marrow mesenchymal stromal cells (BMSCs) favoring adipogenesis over osteogenesis. Altered m6A modifications of BMSCs were confirmed in IBD mice, and further investigation revealed that the SUMOylation of FTO was involved. Nude mice with FTO-K216/357/365R mutation exhibited increased bone sizes and volumes versus control mice. Tocilizumab, an IL-6R monoclonal antibody, combined with AAV-FTO-3KR, mitigated bone loss and enhanced bone formation in IBD mice. Our findings reveal that SUMOylation of FTO is involved in the differentiation of BMSCs in mice with IBDs. The outcome could be blocked by redirecting differentiation toward osteoblasts treatment with AAV-FTO-3KR and the clinical-stage inhibitor, tocilizumab.
2025-06-03 | GSE298548 | GEO
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.
2025-05-29 | GSE278972 | GEO
Project description:Single nucleotide polymorphisms in intron 1 of the fat mass and obesity-associated (FTO) gene were found to be associated with an increased risk of adult obesity. Enhanced FTO expression in mice leads to hyperphagia, increased fat mass, and higher body weight. Neuronal-specific FTOâ??deleted mice have an identical lean body weight phenotype to global FTO-deleted mice. The physiological role of adipose FTO in the homeostasis of energy regulation remains to be elucidated. We used microarrays to elucidate the metabolic pathways that are regulated by FTO in the white fat. FTO flox/flox and Adiponectin-cre FTO flox/flox (AFO) mice were fed with chow diet. White fat tissues from epididymal adipose pad were harvested under ad lib condition for RNA isolation. Three independent pools of FTO flox/flox and AFO mouse white fat RNA were included in the study.
2016-07-03 | E-GEOD-65098 | biostudies-arrayexpress
Project description:SUMOylation, a posttranslational modification, regulates protein function by covalent attachment of small ubiquitin-like modifier (SUMO) proteins to a lysine (Lys) residue on target proteins. Here we use ML-792, a selective SUMO-activating enzyme (SAE) inhibitor, to inhibit global SUMOylation in macrophages derived from bone marrow of C57BL/6 mice. Mouse bone marrow cells isolated from 6–10 weeks C57BL/6 mice were cultured in IMDM medium supplemented with 10% (vol/vol) FBS and 10 ng/mL of macrophage colony-stimulating factor (M-CSF). After 6–8 days of differentiation, the cells were treated with vehicle or ML-792 at 0.5 μM for 24 h. Total RNA was purified using miRNeasy RNA isolation kit (Qiagen) then Ribo-Zero RNA-seq was performed.
2023-10-05 | GSE217604 | GEO
Project description:Here we use MeRIP-Seq to analyze global adenosine methylation (m6A) in mRNAs in the midbrain and striatum of Fto-deficient mice. We find that Fto deficiency leads to increased methylation within a subset of mRNAs important for neuronal signaling, including many within the dopaminergic signaling pathway. Collectively, our results show that Fto regulates demethylation of specific mRNAs in vivo, and this activity relates to control of dopaminergic transmission. Profiling of m6A in midbrain and striatum from FTO knockout mice
2013-06-15 | E-GEOD-47216 | biostudies-arrayexpress
Project description:In this study, we aimed to examine the changes in gene expression that occur in FTO over expressing mice in order to gain more insight into the underlying mechanisms by which FTO influences body weight and adiposity
2014-06-01 | E-MTAB-2331 | biostudies-arrayexpress
Project description:To gain insight into FTO function, we knocked down and overexpressed FTO in HEK293 cells.Genetrail analyses of expression profiles pointed to the RNA splicing and processing machinery. Intriguingly, using immunocytochemistry and confocal laser scanning microscopy, we observed strong enrichment of FTO in nuclear speckles and - to a lesser extent - in nucleoli, but not in other known nuclear bodies. We also studied RNA samples of Fto knockout and wild type mice with regard to content of methylated and unmethylated nucleosidesand observed that ratios of modified and unmodified uracil and adenine were different depending on the presence of FTO. Taken together, our data suggest that FTO is involved in RNA processing and modification. We used microarrays to investigate global gene expression changes depending on the level of FTO We compared FTO overexpressing and FTO depleted cells to cells with endogeneus level of FTO to determine global gene expression changes.
2012-11-13 | E-GEOD-33870 | biostudies-arrayexpress
Project description:The interacted proteins of ALKBH5 and FTO identified by IP-mass
2022-11-03 | MSV000090641 | MassIVE
Project description:We identified the target genes of FTO ("fat mass and obesity associated") in primary cultures of human skeletal muscle cells using adenoviral vectors expressing FTO or GFP and oligonucleotide microarrays. Human myotubes were prepared from 4 different skeletal muscle biopsies. After differentiation, myotubes were infected for 48 hours with recombinant adenovirus expressing either GFP or FTO. Each FTO-infected myotubes culture was compared to GFP-infected myotubes culture. GFP-infected myotubes were regarded as the control. Four biological replicates were processed.
2011-07-05 | E-GEOD-22857 | biostudies-arrayexpress
Project description:In order to comprehensively characterize bone marrow mesenchymal cells after myeloablation, single-nuclei RNA sequencing was performed on bone marrow adipocytes and bone marrow stromal cells isolated from sublethally-irradiated mice.
2023-07-31 | GSE227255 | GEO