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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE171408 | GEO | 2022/03/30

REPOSITORIES: GEO

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

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Genome-wide analysis reveals unique regulation of transcription of Th2-specific genes by GATA3

Project description:Differentiation of naive CD4 T cells into type 2 helper (Th2) cells is accompanied by chromatin remodeling and increased expression of a set of Th2-specific genes including those encoding Th2 cytokines. IL-4-mediated STAT6 activation induces high levels of transcription of GATA3, a master regulator of Th2 cell differentiation, and enforced expression of GATA3 induces Th2 cytokine expression. However, it remains unclear whether the expression of other Th2-specific genes is induced directly by GATA3. A genome-wide unbiased ChIP-seq analysis revealed that GATA3 bound to 1,279 genes selectively in Th2 cells, and 101 genes in both Th1 and Th2 cells. Simultaneously, we identified 26 highly Th2-specific STAT6-dependent inducible genes by a DNA microarray analysis-based three-step selection processes, and among them 17 genes showed GATA3 binding. We assessed dependency on GATA3 for the transcription of these 26 Th2-specific genes, and 10 genes showed increased transcription in a GATA3-dependent manner while 16 genes showed no significant responses. The transcription of the 16 GATA3-nonresponding genes was clearly increased by the introduction of an active form of STAT6, STAT6VT. Therefore, although GATA3 has been recognized as a master regulator of Th2 cell differentiation, many Th2-specific genes are not regulated by GATA3 itself but in collaboration with STAT6. Th1 and Th2 subsets are profiled for mRNA expression Examination of GATA3-binding and 3 different histone modifications in Th1 and Th2 cells.

2011-03-31 | E-GEOD-28292 | biostudies-arrayexpress

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

Project description:The TH1 cell lineage-determining transcription factor T-bet supresses TH2 gene expression by redistributing GATA3 away from TH2 genes

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

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

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

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

| PRJNA719407 | ENA

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