Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA174603 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The complex relationship between Th1 and Th17 cells is incompletely understood. The transcription factor T-bet is best known as the master regulator of Th1 lineage commitment. However, attention is now focused on the repression of alternate T cell subsets mediated by T-bet, particularly the Th17 lineage. Specifically it has recently been suggested that pathogenic Th17 cells express T-bet and are dependent on IL-23. However, T-bet has previously been shown to be a negative regulator of Th17 cells. We have taken an unbiased approach to determine the functional impact of T-bet on Th17 lineage commitment. Genome-wide analysis of functional T-bet binding sites provides an improved understanding of the transcriptional regulation mediated by T-bet, and suggests novel mechanisms by which T-bet regulates T helper cell differentiation. Specifically, we show that T-bet negatively regulates Th17 lineage commitment via direct repression of the transcription factor interferon regulatory factor-4 (IRF4). An in vivo analysis of the pathogenicity of T-bet deficient T cells demonstrated that Th17 responses were augmented in the absence of T-bet, and we have defined a critical temporal window for T-bet function. The interaction of the two key transcription factors T-bet and IRF4 during the determination of T cell fate choice significantly advances our understanding of the mechanisms underlying the development of pathogenic T cells. ChIP-seq analysis of T-bet in WT and Tbet -/- mice.
2013-12-03 | E-GEOD-40623 | biostudies-arrayexpress
Project description:The complex relationship between Th1 and Th17 cells is incompletely understood. The transcription factor T-bet is best known as the master regulator of Th1 lineage commitment. However, attention is now focused on the repression of alternate T cell subsets mediated by T-bet, particularly the Th17 lineage. Specifically it has recently been suggested that pathogenic Th17 cells express T-bet and are dependent on IL-23. However, T-bet has previously been shown to be a negative regulator of Th17 cells. We have taken an unbiased approach to determine the functional impact of T-bet on Th17 lineage commitment. Genome-wide analysis of functional T-bet binding sites provides an improved understanding of the transcriptional regulation mediated by T-bet, and suggests novel mechanisms by which T-bet regulates T helper cell differentiation. Specifically, we show that T-bet negatively regulates Th17 lineage commitment via direct repression of the transcription factor interferon regulatory factor-4 (IRF4). An in vivo analysis of the pathogenicity of T-bet deficient T cells demonstrated that Th17 responses were augmented in the absence of T-bet, and we have defined a critical temporal window for T-bet function. The interaction of the two key transcription factors T-bet and IRF4 during the determination of T cell fate choice significantly advances our understanding of the mechanisms underlying the development of pathogenic T cells.
2013-12-03 | GSE40623 | GEO
Project description:IL-17-producing T helper (TH17) cells have been selected through evolution for their ability to control fungal and bacterial infections. It is also firmly established that their aberrant generation and activation results in autoimmune conditions. Using a characterized potent and selective small molecule inhibitor, we show that the bromodomain and extra-terminal domain (BET) family of chromatin adaptors plays fundamental and selective roles in human and murine TH17 differentiation from naM-CM-/ve CD4+ T cells, as well as in the activation of previously differentiated TH17 cells. We provide evidence that BET controls TH17 differentiation in a bromodomain-dependent manner through a mechanism that includes the direct regulation of multiple effector TH17-associated cytokines, including IL17, IL21 and GMCSF. We also demonstrate that BET family members Brd2 and Brd4 associate with the Il17 locus in TH17 cells, and that this association requires bromodomains. We recapitulate the critical role of BET bromodomains in TH17 differentiation in vivo and show that therapeutic dosing of the BET inhibitor is efficacious in mouse models of autoimmunity. Our results identify the BET family of proteins as a fundamental link between chromatin signaling and TH17 biology, and support the notion of BET inhibition as a point of therapeutic intervention in autoimmune conditions. 4 samples were analyzed: two conditions in duplicate. Naive T cells were placed in conditions leading to TH17 differentiation, with and without BET inhibitor. RNA was collected at 48 hours.
2013-09-20 | E-GEOD-37270 | biostudies-arrayexpress
Project description:IL-17-producing T helper (TH17) cells have been selected through evolution for their ability to control fungal and bacterial infections. It is also firmly established that their aberrant generation and activation results in autoimmune conditions. Using a characterized potent and selective small molecule inhibitor, we show that the bromodomain and extra-terminal domain (BET) family of chromatin adaptors plays fundamental and selective roles in human and murine TH17 differentiation from naïve CD4+ T cells, as well as in the activation of previously differentiated TH17 cells. We provide evidence that BET controls TH17 differentiation in a bromodomain-dependent manner through a mechanism that includes the direct regulation of multiple effector TH17-associated cytokines, including IL17, IL21 and GMCSF. We also demonstrate that BET family members Brd2 and Brd4 associate with the Il17 locus in TH17 cells, and that this association requires bromodomains. We recapitulate the critical role of BET bromodomains in TH17 differentiation in vivo and show that therapeutic dosing of the BET inhibitor is efficacious in mouse models of autoimmunity. Our results identify the BET family of proteins as a fundamental link between chromatin signaling and TH17 biology, and support the notion of BET inhibition as a point of therapeutic intervention in autoimmune conditions.
2013-09-20 | GSE37270 | GEO
Project description:Pharmacological inhibition of chromatin co-regulatory factors represents a clinically validated strategy to modulate oncogenic signaling through selective attenuation of gene expression. Here, we demonstrate that CBP/EP300 bromodomain inhibition preferentially abrogates the viability of multiple myeloma cell lines. Phenotypic effects are preceded by the direct transcriptional suppression of the lymphocyte-specific transcription factor IRF4 and the subsequent down-regulation of the IRF4 transcriptional program. Ectopic expression of IRF4 antagonizes the phenotypic effects of CBP/EP300 bromodomain inhibition and prevents the suppression of the IRF4 target c-MYC. These findings suggest that CBP/EP300 bromodomain inhibition represents a viable therapeutic strategy for targeting multiple myeloma and other lymphoid malignancies dependent on the IRF4 network. Through the use of CBP/EP300 bromodomain inhibitors (CBP/EP300i), we demonstrate that MYC expression in BETi-resistant cells is dependent on CBP/EP300 bromodomains and that treatment with CBP/EP300i restores phenotypic sensitivity.
2016-01-05 | E-GEOD-64317 | biostudies-arrayexpress
Project description:Th17 cells have critical roles in mucosal defense and are major contributors to inflammatory disease. Their differentiation requires the nuclear hormone receptor RORγt working with multiple other essential transcription factors (TFs). We have used an iterative systems approach, combining genome-wide TF occupancy, expression profiling of TF mutants, and expression time series to delineate the Th17 global transcriptional regulatory network. We find that cooperatively-bound BATF and IRF4 contribute to initial chromatin accessibility, and with STAT3 initiate a transcriptional program that is then globally tuned by the lineage-specifying TF RORγt, which plays a focal deterministic role at key loci. Integration of multiple datasets allowed inference of an accurate predictive model that we computationally and experimentally validated, identifying multiple new Th17 regulators, including Fosl2, a key determinant of cellular plasticity. This interconnected network can be used to investigate new therapeutic approaches to manipulate Th17 functions in the setting of inflammatory disease. 143 RNA-seq, 83 ChIP-seq, 65 ChIP-seq controls, and 16 FAIRE-seq
2012-09-20 | E-GEOD-40918 | biostudies-arrayexpress
Project description:IRF4 is critical for differentiation of various CD4+ effector T cells, such as T helper 1 (Th1), Th2, and Th17 subsets, through interaction with BATF-containing AP-1 heterodimers. A major BATF heterodimeric partner, JunB, regulates Th17 differentiation, but the role of JunB in other CD4+ effector T subsets is not fully understood. Here we demonstrate that JunB is essential for accumulation of Th1 and Th2 cells, as well as Th17 cells, both in vitro and in vivo. In mice immunized with lipopolysaccharide (LPS), papain, or complete Freund’s adjuvant (CFA), that induce predominantly Th1, Th2 and Th17 cells, respectively, accumulation of antigen-primed, Junb-deficient CD4+ T cells is significantly impaired. Loss of JunB decreases viability of cells activated under Th1-, Th2-, and Th17-polarizing conditions. RNA-sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) reveal that JunB directly regulates expression of various genes that are commonly induced in priming of naïve CD4+ T cells, including a pro-apoptotic gene Bcl2l11 (encoding Bim), and genes that are specifically induced in Th1, Th2, and Th17 cells. Furthermore, JunB colocalizes with BATF and IRF4 at genomic regions for approximately half of JunB direct target genes. Taken together, JunB, in collaboration with BATF and IRF4, serves a critical function in differentiation of diverse CD4+ T cells by controlling common and lineage-specific gene expression.
2021-10-01 | GSE172490 | GEO
Project description:The transcription factor BATF is required for Th17 and TFH differentiation. Here, we show that BATF also has a fundamental role in regulating effector CD8+ T cell differentiation. BATF-deficient CD8+ T cells show profound defects in effector expansion and undergo proliferative and metabolic catastrophe early after antigen encounter. BATF, together with IRF4 and Jun proteins, binds to and promotes early expression of genes encoding lineage-specific transcription-factors (T-bet and Blimp-1) and cytokine receptors, while paradoxically repressing genes encoding effector molecules (IFNg and granzyme B). Thus, BATF amplifies TCR-dependent transcription factor expression and augments inflammatory signal propagation but restrains effector gene expression. This checkpoint prevents irreversible commitment to an effector fate until a critical threshold of downstream transcriptional activity has been achieved. This is an examination of 5 different transcription factors (TFs) with 5 different histone modifications in effector CD8+ T cells. Two of the TFs (BATF and IRF4) and the histone modifications were replicated. Appropriate control sequence files for ChIP input, IgG ChIP, and Total H3 are also included.
2014-03-02 | E-GEOD-54191 | biostudies-arrayexpress
Project description:Pharmacological inhibition of chromatin co-regulatory factors represents a clinically validated strategy to modulate oncogenic signaling through selective attenuation of gene expression. Here, we demonstrate that CBP/EP300 bromodomain inhibition preferentially abrogates the viability of multiple myeloma cell lines. Phenotypic effects are preceded by the direct transcriptional suppression of the lymphocyte-specific transcription factor IRF4 and the subsequent down-regulation of the IRF4 transcriptional program. Ectopic expression of IRF4 antagonizes the phenotypic effects of CBP/EP300 bromodomain inhibition and prevents the suppression of the IRF4 target c-MYC. These findings suggest that CBP/EP300 bromodomain inhibition represents a viable therapeutic strategy for targeting multiple myeloma and other lymphoid malignancies dependent on the IRF4 network. A total of 13 ChIP-seq samples were sequenced. Samples were treated with control (DMSO) or test compound (2.5 uM SGC-CBP30 or 0.25uM CPI267203) for 6 hours. Signal from input samples was included to subtract background signal from each ChIP-seq sample. Antibodies used were against p300, H3K18ac, H3K27ac, or BRD4.
2016-01-05 | E-GEOD-71909 | biostudies-arrayexpress
Project description:Transcriptional profiling of T-cells isolated from spleen of IRF4 -/- mice and cultured under Th17 polarizing conditions for 42 hrs compared to cells similarly isolated and cultured from spleen of IRF4 +/- mice. The aim of the study was to identify global misexpression of genes in IRF4 -/- cells and hence identify key pathways regulated by IRF4 during Th17 differentiation. Two-condition experiment, IRF4 -/- vs IRF4 +/- Th17 cells at 42hrs. Biological replicates: 3 for each condition
2012-09-13 | E-GEOD-40726 | biostudies-arrayexpress