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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Comparative genomic hybridization and transcription profiling of human and mouse T cells in differentiation

ABSTRACT: ChIP-Chip for T-bet and GATA-3 in human Th1 and Th2 cells, gene expression profiling of human Th1 and Th2 cells and of T-cells from T-bet-deficient mice,

ORGANISM(S): Homo sapiens

SUBMITTER: Richard Jenner

PROVIDER: E-TABM-759 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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The transcription factors T-bet and GATA-3 control alternative pathways of T-cell differentiation through a shared set of target genes.

Jenner Richard G RG Townsend Michael J MJ Jackson Ian I Sun Kaiming K Bouwman Russell D RD Young Richard A RA Glimcher Laurie H LH Lord Graham M GM

Proceedings of the National Academy of Sciences of the United States of America 20091005 42

Upon detection of antigen, CD4(+) T helper (Th) cells can differentiate into a number of effector types that tailor the immune response to different pathogens. Alternative Th1 and Th2 cell fates are specified by the transcription factors T-bet and GATA-3, respectively. Only a handful of target genes are known for these two factors and because of this, the mechanism through which T-bet and GATA-3 induce differentiation toward alternative cell fates is not fully understood. Here, we provide a geno ...[more]

PMID: 19805038

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Genome-wide identification of functional elements regulated by T-bet and GATA3 in human T-cells

Project description:T-bet and GATA3 induce differentiation of CD4+ T-cells into Th1 or Th2 effectors. These exhibit a range of different properties but understanding of T-bet and GATA3 function is mostly limited to the murine Ifng and Il4/Il5/Il13 loci. We hypothesised that extending such analyses across the human genome would allow further insight into T-bet and GATA3 function. We have discovered that T-bet and GATA3 bind to multiple distal sites at a set of key immune regulatory genes. These sites display markers of functional elements, act as enhancers in reporter assays and are associated with lineage-specific expression regulated by T-bet and GATA3. Our approach also reveals that GATA3 is distributed at T-bet binding sites in Th1 cells and that T-bet directly activates its own expression. We propose that these aspects of T-bet and GATA3 function are critical for Th1/ Th2 differentiation and provide a model for the relationship between other lineage-specific regulators. ChIP was performed using antibody against T-bet in Th1 cells and against GATA3 in Th1 cells as well as Th2 cells. A sample of whole cell extract (WCE) from Th1 cells and Th2 cells was sequenced. Th1 WCE was used as the background to determine enrichment.

2012-11-16 | E-GEOD-31320 | biostudies-arrayexpress

Genome-wide regulatory analysis reveals T-bet controls Th17 lineage differentiation through direct suppression of IRF4

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

The Transcription Factor T-bet Is Induced by Multiple Pathways and Prevents an Endogenous Th2 Cell Program during Th1 Cell Responses

Project description:T-bet is a critical transcription factor for T helper 1 (Th1) cell differentiation. To study the regulation and functions of T-bet, we developed a T-bet-ZsGreen reporter mouse strain, in which GFP faithfully reflects the expression of T-bet. By using this tool, we report that signals elicited by IL-12 and IFNg are redundant in inducing T-bet in mice infected with Toxoplasma gondii and that T-bet does not contribute to its own expression when induced by IL-12 and IFNg. While both T-bet and Stat4 are critical for IFNg production, IFNg signaling is dispensable. Strikingly, loss of T-bet results in activation of an endogenous Th2 program in cells expressing T-bet-ZsGreen. Genome-wide analyses suggest T-bet directly induces Th1-related genes but indirectly suppresses Th2-related genes. Our study revealed redundancy and synergy among several Th1-inducing pathways in regulating the expression of T-bet and IFNg, and a critical role of T-bet in suppressing an endogenous Th2 program. RNA-Seq experiments were performed using total RNAs isolated from both wild type and Tbx21-/- Th1 cells in duplicates. Tbet ChIP-seq was performed using wild type Th1 cells. H3K4me1 and H3K27me3 ChIP-seq was performed using both wild type and Tbx21-/- Th1 cells.

2012-10-04 | E-GEOD-38808 | biostudies-arrayexpress

Myo6 regulate transcriptional pause release

Project description:Global run-on sequencing analyses of murine T cells with or without Myosin VI were performed to determine the effect of anti-CD3 stimulation and loss of Myosin VI on the transcription elongation

2015-01-28 | E-MTAB-2381 | biostudies-arrayexpress

STATs Shape the Active Enhancer Landscape of T Cell Populations

Project description:Signaling pathways are intimately involved in cellular differentiation, allowing cells to respond to their environment by regulating gene expression. While enhancers are recognized as key elements that regulate selective gene expression, the interplay between signaling pathways and actively used enhancer elements is not clear. Here, we use CD4+ T cells as a model of differentiation, mapping the acquisition of cell-type-specific enhancer elements in T-helper 1 (Th1) and Th2 cells. Our data establish that STAT proteins have a major impact on the acquisition of lineage-specific enhancers and the suppression of enhancers associated with alternative cell fates. Transcriptome analysis further supports a functional role for enhancers regulated by STATs. Importantly, expression of lineage-defining master regulators in STAT-deficient cells fails to fully recover the chromatin signature of STAT-dependent enhancers. Thus, these findings point to a critical role of STATs as environmental sensors in dynamically molding the specialized enhancer architecture of differentiating cells. Active enhancer elements were defined as p300-high/H3K4me1-high. Using ChIP-seq, we mapped active enhancer landscapes of two CD4+ T helper cells, Th1 and Th2. To investigate the effect of STAT proteins on this landscape, we profiled active enhancers in the absence of STATs. Overall, STATs deficiency had a major impact on recruitment of p300. In addition, ectopic expression of master regulators T-bet and GATA3 in STAT-deficient cells failed to recover most active enhancers.

2012-11-24 | E-GEOD-40463 | biostudies-arrayexpress

Selective inhibition of CD4+ T-cell cytokine production and autoimmunity by BET protein and c-Myc inhibitors

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2012-08-03 | E-GEOD-39886 | biostudies-arrayexpress

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Project description:Study the effect of PARP-14 and its activity on Th2 differentiation ChIP seq was performed on Th2 differentiated cells isolated from PARP-14 +/+ and PARP-14 -/- treated with or without PJ34

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