Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA1132550 | ENA |
REPOSITORIES: ENA
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Project description:Hyperglycemia-triggered lipid peroxidation destabilizes STAT4 and impairs anti-viral Th1 responses in type 2 diabetes
| PRJNA1148141 | ENA
Project description:Type 2 diabetes (T2D) patients are more susceptible to severe respiratory viral infections, but the underlying mechanisms remain elusive. Here, we show that both COVID-19-infected T2D patients and influenza-infected T2D mice exhibit a defective Th1 response, which is an essential component of anti-viral immunity. This defect stems from intrinsic metabolic perturbations in CD4+T cells driven by hyperglycemia. Mechanistically, hyperglycemia triggers mitochondrial dysfunction and excessive fatty acid synthesis, leading to elevated oxidative stress and aberrant lipid accumulation within CD4+T cells. These abnormalities promote lipid peroxidation (LPO), which drives the carbonylation of STAT4, a crucial Th1 lineage-determining factor. Carbonylated STAT4 undergoes rapid degradation, causing reduced T-bet induction and diminished Th1 differentiation. LPO scavenger ameliorates these Th1 defects in T2D patients with poor glycemic control, and restores viral control in T2D mice. Thus, this hyperglycemia-LPO-STAT4 axis underpins reduced Th1 activity in T2D hosts, with important implications for managing T2D-related viral complications.
2024-11-02 | GSE274826 | GEO
Project description:Follicular helper T (Tfh) cells comprise an important subset of helper T cells; however, their relationship with other helper lineages is incompletely understood. Herein, we show IL-12 acting via signal transducer and activator of transcription 4 (STAT4) induced both Il21 and Bcl6 genes, generating cells with features of both Tfh and Th1 cells. However, STAT4 also induced T-bet. Using ChIP-seq, we defined the genome-wide targets of T-bet and found that it repressed Bcl6 and other markers of Tfh cells, thereby attenuating the nascent Tfh-like phenotype in the late phase of Th1 specification. Finally, Tfh-like T cells were rapidly generated following Toxoplasma gondii infection in mice, but T-bet constrained Tfh cells expansion and consequent germinal center formation and antibody production. Our data argue that Tfh and Th1 share a transitional stage through the signal mediated by STAT4, which promotes both phenotypes. However, T-bet represses Tfh functionalities, promoting full Th1 differentiation. The roles of STAT4 and T-bet to determine T helper cell fate were investigated by comparing DNA binding profiles of STAT4 and T-bet in Th1 conditions. The functional outcome was further evaluated by profiling DNase hypersensitivity sites and histone epigenetic marks between WT and STAT4-deficient or T-bet-deficient T cells in Th1 conditions.
2011-12-27 | E-GEOD-33802 | biostudies-arrayexpress
Project description:The Signal Transducer and Activator of Transcription factor STAT4 is a critical component in the development of inflammatory adaptive immune responses. It has been extensively characterized as a lineage-determining factor in Th1 development. However, the genetic program activated by STAT4 that results in an inflammatory cell type is not well defined. In this report we use DNA isolated from STAT4-chromatin immunoprecipitation to perform ChIP-on-chip analysis of over 28,000 mouse gene promoters to identify STAT4 targets. We demonstrate that STAT4 binds multiple gene-sets that program distinct components of the Th1 lineage. While many STAT4 target genes display STAT4-dependent IL-12-inducible expression, other genes displayed IL-12-induced histone modifications but lack induction, possibly due to high relative basal expression. In the subset of genes that STAT4 programs for expression in Th1 cells, IL-12-induced mRNA levels remain increased for a longer time than mRNA from genes that are not programmed. This suggests that STAT4 binding to target genes, while critical, is not the only determinant for STAT4-dependent gene programming during Th1 differentiation. The supplementary bed file contains all 7504 Stat4 binding sites reported in the supplementary Analysis_results.xls Excel file.
2009-06-26 | GSE16845 | GEO
Project description:We report that inhibition and knockout of HDAC6 enhanced Th1 cell differentiation, and decreased Listeria monocytogenes infection in mice. Mechanistically, HDAC6 directly deacetylated CBP-catalyzed acetylation on STAT4 lysine 667 via its enzymatic activity, which is required for IL-12-induced phosphorylation on STAT4. Stat4K667R mutant mice lost the ability to normally differentiate Th1 cell and developed sever L. monocytogenes infection. Our study identifies the STAT4 acetylation on K667 modified dynamically by CBP and HDAC6, as an essential signaling event for Th1 cell differentiation and defense of intracellular pathogen infections, highlighting the therapeutic potential of HDAC6 inhibition for controlling intracellular pathogen infections.
2022-12-15 | GSE146253 | GEO
Project description:There is a close relationship between hyperglycemia in diabetes and progression of periodontal disease. This study aims to investigate the effect of hyperglycemia on the barrier function of gingival epithelial cells as a cause of hyperglycemia-exacerbated periodontitis in diabetes mellitus. Abnormal expressions of adhesion molecules in gingival epithelium in diabetes were compared between db⁄db and control mice.
2023-07-29 | PXD035613 | JPOST Repository
Project description:Fat metabolism is also peturbed after the diagnosis of type 1 diabetes. Patients have less fat in the liver (4) and increased fasting lipid oxidation (5) compared to controls. Similarly, in a BioBreeding rat model of type 1 diabetes, the diabetes-prone animals develop a reduced respiratory quotient compared to non-diabetic rats before the onset of hyperglycemia, consistent with an increased use of fatty acids relative to carbohydrates as an energy substrate (6). We hypothesized that a lack of insulin reaching the liver contributes to the metabolic shift towards lipid oxidation observed in humans with type 1 diabetes and rodent models of the disease. To test our hypothesis, we measured changes in the hepatic gene expression and serum metabolome of a BioBreeding rat model of type 1 diabetes before and after the onset of hyperglycemia.
2017-06-12 | GSE84886 | GEO
Project description:Signal transducer and activator of transcription 4 (STAT4) and STAT6 are key factors in the specification of helper T cells; however, their direct roles in driving differentiation are not well understood. Using chromatin immunoprecipitation and massive parallel sequencing, we quantitated the full complement of STAT-bound genes, concurrently assessing global STAT-dependent epigenetic modifications and gene transcription using cells from cognate STAT-deficient mice. STAT4 and STAT6 each bound over 4000 genes with distinct binding motifs. Both played critical roles in maintaining chromatin configuration and transcription of a core subset of genes through the combination of different epigenetic patterns. Globally, STAT4 had a more dominant role in promoting active epigenetic marks, whereas STAT6 had a more prominent role in antagonizing repressive marks. Clusters of genes negatively regulated by STATs were also identified, highlighting previously unappreciated repressive roles. Therefore, STAT4 and STAT6 play wide regulatory roles in T helper specification. The roles of STAT proteins to shape T helper cell phenotype was investigated by comparing DNA binding profiles of STAT4 and STAT6 in Th1 and Th2 conditions. The functional outcome of STAT bindings was further evaluated by profiling histone epigenetic marks and gene expression changes between WT and STAT-deficient T cells in Th1 and Th2 conditions.
2010-06-18 | E-GEOD-22104 | biostudies-arrayexpress
Project description:Signal transducer and activator of transcription 4 (STAT4) and STAT6 are key factors in the specification of helper T cells; however, their direct roles in driving differentiation are not well understood. Using chromatin immunoprecipitation and massive parallel sequencing, we quantitated the full complement of STAT-bound genes, concurrently assessing global STAT-dependent epigenetic modifications and gene transcription using cells from cognate STAT-deficient mice. STAT4 and STAT6 each bound over 4000 genes with distinct binding motifs. Both played critical roles in maintaining chromatin configuration and transcription of a core subset of genes through the combination of different epigenetic patterns. Globally, STAT4 had a more dominant role in promoting active epigenetic marks, whereas STAT6 had a more prominent role in antagonizing repressive marks. Clusters of genes negatively regulated by STATs were also identified, highlighting previously unappreciated repressive roles. Therefore, STAT4 and STAT6 play wide regulatory roles in T helper specification. The roles of STAT proteins to shape T helper cell phenotype was investigated by comparing DNA binding profiles of STAT4 and STAT6 in Th1 and Th2 conditions. The functional outcome of STAT bindings was further evaluated by profiling histone epigenetic marks and gene expression changes between WT and STAT-deficient T cells in Th1 and Th2 conditions. Affymetrix Mouse Genome 430 2.0 Arrays were used to evaluate global gene expression.
2010-07-07 | E-GEOD-22081 | biostudies-arrayexpress
Project description:Follicular helper T (Tfh) cells comprise an important subset of helper T cells; however, their relationship with other helper lineages is incompletely understood. Herein, we show IL-12 acting via signal transducer and activator of transcription 4 (STAT4) induced both Il21 and Bcl6 genes, generating cells with features of both Tfh and Th1 cells. However, STAT4 also induced T-bet. Using ChIP-seq, we defined the genome-wide targets of T-bet and found that it repressed Bcl6 and other markers of Tfh cells, thereby attenuating the nascent Tfh-like phenotype in the late phase of Th1 specification. Finally, Tfh-like T cells were rapidly generated following Toxoplasma gondii infection in mice, but T-bet constrained Tfh cells expansion and consequent germinal center formation and antibody production. Our data argue that Tfh and Th1 share a transitional stage through the signal mediated by STAT4, which promotes both phenotypes. However, T-bet represses Tfh functionalities, promoting full Th1 differentiation.
2011-12-27 | GSE33802 | GEO