Genome-wide Analyses of Transcription Factor GATA3-Mediated Gene Regulation in Distinct T Cell Types

Laboratory of Molecular Immunology, NHLBI, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Immunity (Impact Factor: 21.56). 08/2011; 35(2):299-311. DOI: 10.1016/j.immuni.2011.08.007
Source: PubMed


The transcription factor GATA3 plays an essential role during T cell development and T helper 2 (Th2) cell differentiation. To understand GATA3-mediated gene regulation, we identified genome-wide GATA3 binding sites in ten well-defined developmental and effector T lymphocyte lineages. In the thymus, GATA3 directly regulated many critical factors, including Th-POK, Notch1, and T cell receptor subunits. In the periphery, GATA3 induced a large number of Th2 cell-specific as well as Th2 cell-nonspecific genes, including several transcription factors. Our data also indicate that GATA3 regulates both active and repressive histone modifications of many target genes at their regulatory elements near GATA3 binding sites. Overall, although GATA3 binding exhibited both shared and cell-specific patterns among various T cell lineages, many genes were either positively or negatively regulated by GATA3 in a cell type-specific manner, suggesting that GATA3-mediated gene regulation depends strongly on cofactors existing in different T cells.

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    • "Indeed, some high profile studies have restricted their analysis of TF binding sites to the minority of sites located in the vicinity of genes that change expression following external stimulation or TF knock-down (Garber et al, 2012). Another important observation gained from ChIP-Seq studies concerns the realisation that global binding patterns for a given TF can be very distinct in different cell types (Wei et al, 2011) and indeed may correlate more strongly with other TFs in the same cell type than with itself across different cell types (Hannah et al, 2011). Of note, the cell type-specific nature of global binding patterns has also been observed for so-called master regulator TFs (Lodato et al, 2013), therefore raising the question as to how a " master regulator " can dictate cell type identity, when in fact it appears that its own global binding patterns are largely driven by the cellular environment? "
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    • "Even with this potent stimulus, IL-13 production was dramatically decreased in Gata3-deficient cells (Figure S4F) suggesting that GATA3 directly regulates IL-13 production in ILC2s, independent of its role in maintaining IL-33R expression. This is consistent with the established capacity of GATA3 to directly bind to the promoter of the Il13 gene in many T cell subsets (Wei et al., 2011). "
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    • "One additional expectation for developmentally regulated promoters is that they should be bound by tissue specific transcription factors. To test this, we analyzed ChIP-seq data performed in DP thymocytes for a series of lymphoid-specific transcription factors, including GATA3 [39], Ikaros [40], ETS1 [32] and RUNX1 (this study). These transcription factors were found in a higher frequency at LUAT-associated promoters active in DP thymocytes, as compared with a set of control genes (Figure 5G). "
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