Loss function of Fkbp5 leads to gene network alterations related to neuron development, mitochondria morphology, and calcium permissiveness at baseline and in alcohol stimulation conditions
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE143354 | GEO | 2026/01/02
REPOSITORIES: GEO
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Project description:Loss function of Fkbp5 leads to gene network alterations related to neuron development, mitochondria morphology, and calcium permissiveness at baseline and in alcohol stimulation conditions
| PRJNA600234 | ENA
Project description:To better our understanding and obtain a mechanistic insight on the role of FKBP5 on alcohol-induced liver injury, we performed RNA-seq analysis and compared the alterations in gene expression from WT and Fkbp5-/- mice on ethanol and pair-fed diet.
2023-07-23 | GSE155830 | GEO
Project description:FKBP5 is a long glucocorticoid-inducible gene implicated in psychiatric disorders. To investigate the complexities of chromatin interaction frequencies at the FKBP5 topologically associated domain (TAD), we deployed fifteen one-to-all chromatin capture viewpoints near gene promoters, enhancers, introns, and CTCF-loop anchors. This revealed a ‘one-TAD-one-gene’ structure encompassing the FKBP5 promoter and its enhancers. The FKBP5 promoter and its two glucocorticoid-stimulated enhancers roam the entire TAD while displaying subtle cell type-specific interactomes. The FKBP5 TAD consists of two nested CTCF loops that are coordinated by one CTCF site beyond the FKBP5 polyadenylation site and another in its 8th intron, 61 kb further. Loop extension correlates with transcription increases through the intronic CTCF site. This is efficiently compensated for, since the short loop is restored even under high transcription regimes. The boundaries of the FKBP5 TAD consist of divergent CTCF sites, harbor multiple smaller genes and are resilient to glucocorticoid stimulation. Interestingly, both FKBP5 TAD boundaries harbor H3K27me3-marked heterochromatin blocks that may reinforce them. We propose that cis-acting genetic and epigenetic polymorphisms underlying FKBP5 expression variation are likely to reside within a 240 kb region that consists of the FKBP5 TAD, its left sub-TAD, and both its boundaries.
2023-10-15 | GSE136034 | GEO
Project description:FKBP51, also known as FK506-binding protein 51, is a molecular chaperone and scaffolding protein with significant roles in regulating hormone signaling and stress responding. Genetic variants in FKBP5, which encodes FKBP51, have been implicated in a growing number of neuropsychiatric disorders, which has spurred efforts to target FKBP51 therapeutically. However, the molecular mechanisms by which FKBP51 influences the pathways affected in these disorders are not fully understood. Protein changes in Fkbp5 KO mice, as measured by histology and proteomics, revealed alterations in a brain region- and sex-dependent manner.
2024-09-05 | PXD049439 | Pride
Project description:The disturbance of immune balance at the maternal-fetal interface is a significant contributor to obstetric antiphospholipid syndrome (OAPS); however, the precise mechanisms underlying this disturbance remain unclear. This study investigates the immune regulatory role of FK506-binding protein 5 (FKBP5) to elucidate its molecular mechanisms in pathological pregnancies associated with OAPS. We conducted RNA sequencing (RNA-seq) analysis and immune cell typing on decidual tissue from OAPS patients and healthy controls. The results indicated that the FKBP5 gene and inflammation-related pathways were significantly expressed in the maternal-fetal interface of OAPS patients, characterized by an increase in M1 (iNOS+/CD86+) macrophages and a decrease in M2 (Arg-1+/CD206+) macrophages. In vitro experiments demonstrated that FKBP5 promotes M1-like polarization of macrophages via the JAK1/STAT1 pathway while inhibiting M2-like polarization through the PPARγ/STAT6 pathway. Using a macrophage-trophoblast cell co-culture model, we found that FKBP5-induced abnormal macrophage polarization at the maternal-fetal interface negatively impacted the migration, invasion, and proliferation of trophoblast cells. In a mouse model of OAPS, the knockout of FKBP5 regulated the abnormal polarization of macrophages between M1 and M2 phenotypes, facilitated epithelial-to-mesenchymal transition (EMT), and mitigated antiphospholipid antibodies (aPLs)-mediated placental pathological damage. Notably, SAFit2, a small molecule inhibitor of FKBP5, effectively improved adverse pregnancy outcomes in OAPS mice. The immune microenvironment imbalance at the maternal-fetal interface, driven by FKBP5-regulated macrophage polarization, constitutes a critical immunological basis for aPLs-mediated placental damage. Therefore, FKBP5 presents a potential therapeutic target for OAPS.
2025-04-07 | GSE283798 | GEO
Project description:Background: Inhalation anesthetics may trigger the hypothalamic–pituitary–adrenal (HPA) axis. FK-506 binding protein (FKBP5) is a critical factor that regulates the HPA axis and is associated with perioperative neurocognitive impairment. However, it is unclear how inhalation anesthetics affects the expression of FKBP5 in different neural cells in the brain. Methods: We used single-nucleus RNA sequencing to characterize hippocampal transcriptome profiles in the brains of aged marmosets and mice after sevoflurane anesthesia. Results: Higher levels of FKBP5 were found in the hippocampi of aged mice after sevoflurane anesthesia. Single nuclear RNA sequencing results from aged mice and marmosets showed that the increased expression of FKBP5 mainly occurred in microglia. The expression of FKBP5 in the hippocampi of aged marmosets and mice increased following long-term exposure to sevoflurane anesthesia. Additionally, the brains of these animals displayed a marked increase in the expression of FKBP5 in microglia after sevoflurane anesthesia. Conclusion: Long-term exposure to sevoflurane augments FKBP5 expression in the hippocampi of aged marmosets and mice, specifically in the microglia.
2024-10-30 | GSE234493 | GEO
Project description:While the paradigm that genetic predisposition and environmental exposures interact to shape development and function of the human brain and ultimately the risk of psychiatric disorders has drawn wide interest, the corresponding molecular mechanisms have not been elucidated yet. Here we show that a functional polymorphism altering chromatin interaction between the transcription start site and long range enhancers in the FK506 binding protein 5 (FKBP5) gene, an important regulator of the stress hormone system, increases the risk of developing stress-related psychiatric disorders in adulthood by allele-specific, childhood trauma-dependent DNA demethylation in functional glucocorticoid response elements (GREs) of FKBP5. This demethylation is linked to increased stress-dependent gene transcription followed by a long-term dysregulation of the stress hormone system and a global impact on the function of immune cells and brain areas associated with stress regulation. This first identification of molecular mechanisms of genotype-directed long-term environmental reactivity will also critically contribute to designing more effective treatment strategies for stress-related disorders. Effects of FKBP5 rs1360780 genotype x environment interaction on peripheral blood mRNA expression of GR responsive genes, as measured by gene expression arrays, were explored in 129 individuals (child abuse/risk allele carrier N = 40, child abuse/protective allele carrier N = 15; and no child abuse/risk allele carrier N = 60, no child abuse/protective allele carrier N = 14). In all 129 individuals, 1627 transcripts showed a significant correlation with plasma cortisol concentrations, suggesting their GR responsiveness. The correlation of 76 of these transcripts with cortisol plasma levels showed significant differences when stratifying by FKBP5 genotype in individuals with child abuse (Fisher z score ≥ 1.96) For these 76 transcripts, the mean absolute correlation coefficient with plasma cortisol was R = 0.23 in the risk allele carriers with child abuse, that is those exhibiting a demethylation of FKBP5 intron 7 as compared to R = 0.74 in the carriers of the protective genotype with child abuse where intron 7 methylation remains largely stable. This indicates a relative GR-resistance in the trauma exposed FKBP5 risk allele vs. protective genotype carriers. These 76 transcripts did not show a genotype-dependent difference in correlation coefficients in non-trauma exposed individuals suggesting that exposure to early trauma enhances FKBP5 genotype-dependent effect of GR sensitivity, most likely by epigenetic mechanisms. These findings suggest that the combination of FKBP5 risk allele carrier status and early trauma exposure alters the stress hormone-dependent regulation of several genes in peripheral blood cells, and might thereby enhance the reported association of early trauma with immune and inflammatory dysregulation, further promoting system-wide symptoms of stress-related disorders.
2012-11-03 | E-GEOD-42002 | biostudies-arrayexpress
Project description:FK506-binding protein 51 (FKBP51, encoded by FKBP5) is a multisignaling cochaperone that regulates cellular stress responses and inflammatory signaling through the NF-κB pathway. Although FKBP51 is upregulated in reactive astrocytes, its role in epilepsy and excitotoxic neuroinflammation remains unknown. Excessive astrogliosis and impaired glutamate transporter-1 (GLT-1)-mediated glutamate clearance promote excitotoxicity and increase seizure susceptibility. Here, we investigated how both global and astrocyte-specific Fkbp5 deletions influence seizure susceptibility, astrogliosis, neuroinflammation, and cognition in male mice subjected to a kainic acid (KA)-induced epilepsy mouse model. Global Fkbp5 knockout (Fkbp5-KO) presented lower seizure activity along with decreased neuronal loss and astrogliosis in the hippocampus compared with the wild-type mice. Astrocyte-specific Fkbp5 conditional knockout (aFkbp5-cKO) mice similarly attenuated seizure severity, decreased astrogliosis, improved novel object recognition, and preserved GLT-1 expression in hippocampal CA3. Glia-neuron mixed cultures derived from Fkbp5-KO brains showed reduced NMDA-induced neurotoxicity and astrogliosis, accompanied by decreased NF-κB p65 phosphorylation. Notably, overexpression of an Fkbp5 quadruple mutant that disrupts the FKBP51-NF-κB interaction inhibited proinflammatory lipopolysaccharide-induced astrogliosis and NF-κB activation. Transcriptomic analysis of Fkbp5-KO hippocampi further confirmed suppression of NF-κB-driven inflammatory pathways. In summary, astrocytic FKBP51 mediates reactive astrogliosis and GLT-1 downregulation, linking excitotoxic neuroinflammation with seizure susceptibility and cognitive impairment, and represents a potential intervention target for epilepsy.
2026-02-02 | GSE293536 | GEO
Project description:Glucocorticoid excess is linked to central obesity, adipose tissue insulin resistance and type 2 diabetes mellitus. The aim of our study was to investigate the effects of dexamethasone on gene expression in human subcutaneous and omental adipose tissue, in order to identify potential novel mechanisms and biomarkers for glucocorticoid-induced insulin resistance in adipose tissue. Dexamethasone changed the expression of 527 genes in both subcutaneous and omental adipose tissue. FKBP5 and CNR1 were the most responsive genes in both depots (~7-fold increase). Dexamethasone increased FKBP5 gene and protein expression in a dose-dependent manner in both depots, but FKBP5 protein levels were 10-fold higher in omental than subcutaneous adipose tissue. FKBP5 gene expression in subcutaneous adipose tissue was positively correlated with serum insulin, HOMA-IR and subcutaneous adipocyte diameter, while fold change in gene expression by dexamethasone was negatively correlated with clinical markers of insulin resistance, i.e. HbA1c, BMI, HOMA-IR and serum insulin. Only one gene, SERTM1, clearly differed in response to dexamethasone between the two depots. Dexamethasone at high concentrations, influences gene expression in both subcutaneous and omental adipose tissue in a similar pattern and promotes gene expression of FKBP5, a gene that may be implicated in glucocorticoid-induced insulin resistance. Paired human subcutaneous (sc) and omental (om) adipose tissue samples obtained from 4 non-diabetic adipose tissue donors (4 M; BMI: 20.8-27.5 Kg/m2) were incubated without (Ctr) or with dexamethasone (Dex, 3 M-NM-<M) for 24 h.
2014-08-18 | E-GEOD-42902 | biostudies-arrayexpress
Project description:Facial infiltrating lipomatosis (FIL) is a congenital disorder characterized by unilateral facial enlargement. Although next-generation sequencing has revealed that the pathogenesis of FIL is associated with phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) mutations, the underlying molecular mechanisms remain undetermined. We found that the adipose tissue in FIL patients demonstrated tissue infiltration accompanied by adipocytes hypertrophy and increased lipid accumulation. All FIL derived fibro-adipose progenitor cells (FIL-FAPs) harboured PIK3CA mutations. Compared to FAPs obtained from normal subcutaneous adipose tissue, FIL-FAPs exhibited a greater capacity for adipogenesis. Suppression of PIK3CA resulted in a reduction in the adipogenic potential of FIL-FAPs. Through single cell sequencing, we find that FIL-FAPs had higher expression of FKBP5. Inhibiting FKBP5 can impair the adipogenic capacity of FIL-FAPs. We also verified that PI3K-AKT pathway regulating FKBP5 expression. To find the downstream target of FKBP5, we performed RNA-seq of FIL-FAPs treated with FKBP5 inhibitor SAFit2 in DMSO or DMSO alone.
2025-08-08 | GSE279487 | GEO