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Omics score: 5

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,

SUBMITTER: Richard Jenner

PROVIDER: E-TABM-759 | ArrayExpress | 2009-10-26

REPOSITORIES: ArrayExpress

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Publications

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 | 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 | 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 | 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 | ArrayExpress

Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells

Project description:CD4(+) type 1 T regulatory (Tr1) cells are induced in the periphery and have a pivotal role in promoting and maintaining tolerance. The absence of surface markers that uniquely identify Tr1 cells has limited their study and clinical applications. By gene expression profiling of human Tr1 cell clones, we identified the surface markers CD49b and lymphocyte activation gene 3 (LAG-3) as being stably and selectively coexpressed on mouse and human Tr1 cells. We showed the specificity of these markers in mouse models of intestinal inflammation and helminth infection and in the peripheral blood of healthy volunteers. The coexpression of CD49b and LAG-3 enables the isolation of highly suppressive human Tr1 cells from in vitro anergized cultures and allows the tracking of Tr1 cells in the peripheral blood of subjects who developed tolerance after allogeneic hematopoietic stem cell transplantation. The use of these markers makes it feasible to track Tr1 cells in vivo and purify Tr1 cells for cell therapy to induce or restore tolerance in subjects with immune-mediated diseases. The transcriptome of human Tr1 cell clones to that of TH0 cell clones either unstimulated or stimulated for 6 and 16 h. Tr1 and TH0 cell clones were isolated from peripheral blood of 2 Healthy Donors (HDs). mRNA from T cell clones unstimulated (t0, n=4 Tr1 cell clones and n=10 TH0 cell clones) or stimulated with immobilized anti-CD3 and soluble anti-CD28 mAbs (6h and 16h, n=4 Tr1 cell clones and n=5 TH0 cell clones) was isolated. Differential expression of 28869 genes was investigated by whole transcript Affymetric chips.

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Study the effect of PARP-14 and its activity on Th2 differentiation

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

2013-12-31 | E-GEOD-51344 | ArrayExpress

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

Project description:Bromodomain-containing proteins bind acetylated lysine residues on histone tails and are involved in the recruitment of additional factors that mediate histone modifications and enable transcription. A compound, I-BET-762, that inhibits binding of an acetylated histone peptide to BRD4 and other proteins of the BET (bromodomain and extra-terminal domain) family, was previously shown to suppress the production of pro-inflammatory proteins by macrophages and block acute inflammation in mice. Here we investigate the effect of I-BET-762 on T cell function. We show that treatment of naïve CD4+ T cells with I-BET-762 during early differentiation modulates subsequent cytokine production, and inhibits the ability of Th1-skewed cells to induce autoimmune pathogenesis in a model of experimental autoimmune encephalomyelitis (EAE) in vivo. The suppressive effects of I-BET-762 on T-cell mediated inflammation were not due to inhibition of expression of the pro-inflammatory cytokines, IFN-. or IL-17, but correlated with the ability to suppress GM-CSF production from CNS-infiltrating T cells, resulting in decreased recruitment of macrophages and granulocytes. The effects of I-BET-762 were distinct from those of the fumarate ester, dimethyl fumarate (DMF), a candidate drug for treatment of multiple sclerosis (MS). Our data suggest that I-BET and DMF could have complementary roles in the treatment of MS, and provide a strong rationale for inhibitors of BET-family proteins in the treatment of autoimmune diseases, based on their dual ability to suppress granulocyte and macrophage recruitment by T cells as well as production of pro-inflammatory proteins by macrophages. RNA from resting or activated CD4+ T cells grown in the presence of a control substance (DMSO or Control-768) or two different concentrations of I-BET-762, was hybridized to the chip. There are 3 biological replicates for a total of 2 (cell states) x 4 (conditions) x 3 (replicates) = 24 samples.

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T-bet and GATA-3 act in combination through distal regulatory elements across the genome

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Expression and functions of long noncoding RNAs during human T helper cell differentiation

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