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T-bet recruits P-TEFb to super-enhancers to regulate T helper cell differentiation (Agilent 2)

ABSTRACT: The transcription factor T-bet induces differentiation of CD4+ T cells into the Th1 lineage and also allows for a degree of functional plasticity. Here, we show that T-bet acts through super-enhancers to recruit the elongation factor P-TEFb. Th1-specific genes are poised for activation in Th2 cells and P-TEFb recruitment activates transcriptional elongation. T-bet also induces extensive P-TEFb binding at super-enhancers, where it acts to stimulate enhancer RNA transcription. P-TEFb inhibition selectively blocks activation of lineage-specific genes and reverses Th1-associated retinitis pathology. T-bet-mediated recruitment of P-TEFb to super-enhancers at otherwise poised genes provides a model for how lineage-specifying factors promote differentiation towards specific cell fates whilst maintaining a degree of functional plasticity. Transcriptional profiling of mouse Th1 and Th2 cells treated with JQ1, which inhibits P-TEFb recruitment, or the P-TEFb inhibitor Flavopiridol vs DMSO conrol treated cells. Goal was to identify genes which are sensitive to P-TEFb inhibition.

ORGANISM(S): Mus musculus

PROVIDER: GSE62485 | GEO | 2016/06/08

SECONDARY ACCESSION(S): PRJNA264232

REPOSITORIES: GEO

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T-bet recruits P-TEFb to super-enhancers to regulate T helper cell differentiation (Agilent 1)

Project description:The transcription factor T-bet induces differentiation of CD4+ T cells into the Th1 lineage and also allows for a degree of functional plasticity. Here, we show that T-bet acts through super-enhancers to recruit the elongation factor P-TEFb. Th1-specific genes are poised for activation in Th2 cells and P-TEFb recruitment activates transcriptional elongation. T-bet also induces extensive P-TEFb binding at super-enhancers, where it acts to stimulate enhancer RNA transcription. P-TEFb inhibition selectively blocks activation of lineage-specific genes and reverses Th1-associated retinitis pathology. T-bet-mediated recruitment of P-TEFb to super-enhancers at otherwise poised genes provides a model for how lineage-specifying factors promote differentiation towards specific cell fates whilst maintaining a degree of functional plasticity. Transcriptional profiling of human Th1 and Th2 cells

2016-06-08 | GSE62484 | GEO

T-bet recruits P-TEFb to super-enhancers to regulate T helper cell differentiation (RNA-Seq)

2016-06-08 | GSE62483 | GEO

T-bet activates poised Th1 genes through Mediator and the Super Elongation Complex [ChIP-Seq]

Project description:The transcription factor T-bet directs Th1 cell differentiation, but the molecular mechanisms that underlie this lineage-specific gene regulation are not completely understood. Here, we show that T-bet acts through super-enhancers in human and mouse Th1 cells to recruit Mediator and P-TEFb in the form of the super elongation complex (SEC). Th1-specific genes are poised in Th2 cells while T-bet-mediated recruitment of P-TEFb in Th1 cells activates transcriptional elongation. P-TEFb is recruited to both genes and super-enhancers, where it activates enhancer RNA transcription. P-TEFb inhibition and Mediator and SEC knockdown selectively block activation of T-bet target genes and P-TEFb inhibition abrogates Th1-associated experimental autoimmune uveitis. T-bet activity is independent of changes in NF-κB RelA and Brd4 binding, but T-bet- and NF-κB-mediated pathways converge to allow P-TEFb recruitment. These data support a model in which lineage-specifying factors allow recruitment of P-TEFb to poised genes to promote differentiation of alternative T cell fates.

2016-06-08 | GSE62482 | GEO

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

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

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

2012-11-16 | GSE31320 | GEO

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

Project description: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,

2009-10-26 | E-TABM-759 | 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

Discovery and Characterization of Super-Enhancer Associated Dependencies in Diffuse Large B-Cell Lymphoma

Project description:Diffuse Large B-Cell Lymphoma (DLBCL) is a biologically heterogeneous and clinically aggressive disease. Here, we explore the role of BET bromodomain proteins in DLBCL, using integrative chemical genetics and functional epigenomics. We observe highly asymmetric loading of BRD4 at enhancers, with approximately 33% of all BRD4 localizing to enhancers at 1.6% of occupied genes. These super-enhancers prove particularly sensitive to bromodomain inhibition, explaining the selective effect of BET inhibitors on oncogenic and lineage-specific transcriptional circuits. Functional study of genes marked by super-enhancers identifies DLBCLs dependent on OCA-B and suggests a strategy for discovering unrecognized cancer dependencies. Translational studies performed on a comprehensive panel of DLBCLs establish a therapeutic rationale for evaluating BET inhibitors in this disease. ChIP-Seq for various transcription factors and histone modifications in diffuse large B-cell lymphoma cells

2013-12-10 | E-GEOD-46663 | biostudies-arrayexpress

The TH1 cell lineage-determining transcription factor T-bet supresses TH2 gene expression by redistributing GATA3 away from TH2 genes [RNA-seq]

Project description:Differentiation of progenitor cells into mature cell types is commonly associated with the expression of lineage-determining transcription factors (LD-TFs) specific to that lineage. In CD4+ T cells, T-bet dictates differentiation of the TH1 lineage, whereas GATA3 drives differentiation of the alternative TH2 lineage. LD-TFs, including T-bet and GATA3, are frequently co-expressed, both in vitro and in vivo. How co-expression of two mutually antagonistic LD-TFs affects their function and lineage determination is not known. By expressing T-bet and GATA3 separately or together, we show that T-bet sequesters GATA3 at its target sites, thereby removing GATA3 from TH2 genes. T-bet interacts with the GATA3 DNA binding domain, changing its DNA sequence binding preference. This mechanism allows T-bet to dominate and drive the TH1 gene expression program in the presence of the GATA3. We propose that redistribution of one LD-TF by another may be a common mechanism that could explain how specific cell fate choices can be made even in the presence of other TFs driving alternative differentiation pathways.

2022-03-30 | GSE171409 | GEO

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