Iron-Dependent KDM4D Activity Controls the Quiescence-Activity Balance of MSCs via the PI3K-Akt-Foxo1 Pathway
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1029564 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Iron deficiency is a common nutritional deficit that can lead to organ damage or dysfunction. Research is increasingly linking iron deficiency to dysfunction of bone metabolism, although the exact mechanisms remain unclear. Some studies suggest that iron-dependent methylation-erasing enzyme activity regulates cell proliferation and differentiation under physiological or pathological conditions. Whether iron deficiency inhibits the activation of quiescent mesenchymal stem cells (MSCs) by affecting histone demethylase activity is unclear. In our study, we discovered that KDM4D plays a pivotal role in the activation of quiescent MSCs. Under conditions of iron deficiency, the H3K9me3 demethylase activity of KDM4D significantly decreased. This change led to increased heterochromatin with H3K9me3 near the PIK3R3 promoter, hindering the expression of PIK3R3. Subsequently, the activation of quiescent MSCs was inhibited via the PI3K-Akt-Foxo1 pathway. Iron-deficient mice exhibited significantly inhibited bone marrow MSC activation and reduced bone mass compared to normal mice. Modulating the PI3K-Akt-Foxo1 pathway could reverse iron deficiency-induced bone loss.
2024-07-01 | GSE245684 | GEO
Project description:Iron deficiency is a common nutritional deficit that can lead to organ damage or dysfunction. Research is increasingly linking iron deficiency to dysfunction of bone metabolism, although the exact mechanisms remain unclear. Some studies suggest that iron-dependent methylation-erasing enzyme activity regulates cell proliferation and differentiation under physiological or pathological conditions. Whether iron deficiency inhibits the activation of quiescent mesenchymal stem cells (MSCs) by affecting histone demethylase activity is unclear. In our study, we discovered that KDM4D plays a pivotal role in the activation of quiescent MSCs. Under conditions of iron deficiency, the H3K9me3 demethylase activity of KDM4D significantly decreased. This change led to increased heterochromatin with H3K9me3 near the PIK3R3 promoter, hindering the expression of PIK3R3. Subsequently, the activation of quiescent MSCs was inhibited via the PI3K-Akt-Foxo1 pathway. Iron-deficient mice exhibited significantly inhibited bone marrow MSC activation and reduced bone mass compared to normal mice. Modulating the PI3K-Akt-Foxo1 pathway could reverse iron deficiency-induced bone loss.
2024-07-01 | GSE245685 | GEO
Project description:Iron-Dependent KDM4D Activity Controls the Quiescence-Activity Balance of MSCs via the PI3K-Akt-Foxo1 Pathway [CUT&Tag]
| PRJNA1029575 | ENA
Project description:One major effect of PI3-kinase activation downstream of the serine/threonine kinase Akt is the phosphorylation of the transcription factor FOXO1 and its neutralization. FOXO1 has several ubiquitous targets genes in many cell types that control cell quiescence, oxydative stress or apoptosis. However, it has been demonstrated that FOXO1 also has specific targets depending of the cellular context. The role of FOXO1 to regulate specific genes in T lymphocytes has not been investigated yet. To examine this point, we used the CD4+ leukemia Jurkat T-cell line, in which the PI3K pathway is constitutively turned-on and FOXO1 transcriptional activity strongly repressed. These cells were transduced with lentiviruses coding for a constitutively active form of FOXO1 fused to GFP and having the three AKT phosphorylation sites mutated to alanine (FOXO1-AAA-GFP) to restore its transcriptional activity. GFP-transduced cells were used as a control and the gene activation levels in the two cell populations analyzed 48 hours post-infection.
2008-12-01 | E-TABM-391 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-07-01 | GSE245686 | GEO
Project description:PI3K signaling and FOXO transcription factors play opposing roles at several B cell developmental stages. We show here abundant nuclear FOXO1 expression in the proliferative compartment of the germinal center (GC), its dark zone (DZ), and PI3K activity, downregulating FOXO1, in the GC light zone (LZ), where cells are selected for further differentiation. However, here FOXO1 is expressed in c-Myc+ cells destined for DZ reentry. Upon FOXO1 ablation by genetic means or induction of PI3K activity GCs become devoid of their DZ, due at least partly to the downregulation of the chemokine receptor CXCR4. While this is known to prevent proper cyclic selection of cells expressing high-affinity antibodies, the initiation of immunoglobulin switching is essentially dependent on FOXO1 activity. All samples were obtained from mouse germinal center (GC) B cells (Cgamma1-cre; YFP, P110*, FOXO1 f/f or PTEN f/f animals). Cells used for microarray analysis were FACS sorted cells.
2015-11-23 | E-GEOD-68043 | biostudies-arrayexpress
Project description:PAX3-FOXO1 is a fusion transcription factor that is the main driver of tumorigenesis leading to the development of alveolar rhabdomyosarcoma (aRMS). Since aRMS cells are addicted to PAX3-FOXO1 activity, the fusion protein also represents a major target for therapeutic interference, which is however challenging as transcription factors usually cannot be inhibited directly by small molecules. Hence, characterization of the biology of PAX3-FOXO1 might lead to the discovery of new possibilities for an indirect inhibition of its activity. Here, our goal was to characterize the proteomic neighborhood of PAX3-FOXO1 and to find candidates potentially affecting its activity and tumor cell viability. Towards this aim, we expressed BirA fused versions of PAX3-FOXO1 (N- and C-terminal) in HEK293T cells under presence of biotin. In the control setup, we expressed the BirA enzyme alone. After Streptavidin purification of biotinylated proteins, we performed mass spectrometry and quantified relative abundances compared to control conditions. This enabled us to determine PAX3-FOXO1 proximal proteins, which we investigated further in orthogonal endogenous systems.
2021-09-16 | PXD022187 | Pride
Project description:Fusion-positive alveolar rhabdomyosarcoma (FP-RMS) is an aggressive pediatric sarcoma driven primarily by the PAX3-FOXO1 fusion oncogene, for which therapies targeting PAX3-FOXO1 are lacking. We screened 62,643 compounds using an engineered cell line that monitors PAX3-FOXO1 transcriptional activity identifying a hitherto uncharacterized compound, PFI-63. RNA-seq, ATAC-seq, and docking analyses implicated histone lysine demethylases (KDMs) as its targets. Enzymatic assays confirmed the inhibition of multiple KDMs with highest selectivity for KDM3B. Structural similarity search of PFI-63 identified PFI-90 with improved solubility and potency. Biophysical binding of PFI-90 to KDM3B was demonstrated using NMR and SPR. PFI-90 suppressed the growth of FP-RMS in vitro and in vivo through downregulating PAX3-FOXO1 activity, and combined knockdown of KDM3B and KDM1A phenocopied PFI-90 effects. Thus, we report novel KDM inhibitors with highest specificity for KDM3B. Its potent suppression of PAX3-FOXO1 activity can be exploited as a new therapeutic approach for FP-RMS and other transcriptionally driven cancers.
2023-12-31 | GSE219199 | GEO
Project description:Tight regulation of Toll-like receptor (TLR)-mediated inflammatory responses is important in innate immunity. Here, we show that T cell death-associated gene 51 (TDAG51/PHLDA1) is a novel coactivator of the transcription factor FoxO1, regulating inflammatory mediator production in the lipopolysaccharide (LPS)-induced inflammatory response. TDAG51 induction by LPS stimulation was mediated by the TLR2/4 signaling pathway in bone marrow-derived macrophages (BMMs). LPS-induced inflammatory mediator production was significantly decreased in TDAG51-deficient BMMs. In TDAG51-deficient mice, LPS- or pathogenic Escherichia coli infection-induced lethal shock was reduced by decreasing serum proinflammatory cytokine levels. The recruitment of 14-3-3 to FoxO1 was competitively inhibited by the TDAG51-FoxO1 interaction, leading to blockade of FoxO1 cytoplasmic translocation and thereby strengthening FoxO1 nuclear accumulation. TDAG51/FoxO1 double-deficient BMMs showed significantly reduced inflammatory mediator production compared with TDAG51- or FoxO1-deficient BMMs. TDAG51/FoxO1 double deficiency protected mice against LPS- or pathogenic E. coli infection-induced lethal shock by weakening the systemic inflammatory response. Thus, these results indicate that TDAG51 acts as a coactivator of the transcription factor FoxO1, leading to strengthened FoxO1 activity in the LPS-induced inflammatory response.
2023-06-24 | PXD039815 | Pride