A Gata3 enhancer necessary for ILC2 development and function
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE169542 | GEO | 2021/07/22
REPOSITORIES: GEO
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Project description:Innate lymphoid cells (ILCs) play critical roles during innate immune responses to pathogens and lymphoid organ development. IL-7Ra+ ILC subsets, similar to T helper (Th) cell subsets, produce distinctive effector cytokines. The molecular control of IL-7Ra+ ILC development and maintenance has yet to be dissected. Here we report that GATA3 is indispensable for the development of all IL-7Ra+ ILC subsets and T cells. Gata3 conditional deficient mice have no lymph nodes and are susceptible to Citrobactor rodentium infection. Genome-wide gene analyses indicate that GATA3 regulates similar set of cytokines and receptors in ILC2s and Th2 cells and is critical for the maintenance of ILC2s. Thus, GATA3 plays parallel roles in establishing and regulating both adaptive and innate lymphocytes. To identify GATA3 regulated genes in type 2 innate lymphoid cells by tamoxifen-mediated acute deletion of Gata3 gene.
2014-03-13 | E-GEOD-47851 | biostudies-arrayexpress
Project description:Innate lymphoid cells (ILCs) play critical roles during innate immune responses to pathogens and lymphoid organ development. IL-7Ra+ ILC subsets, similar to T helper (Th) cell subsets, produce distinctive effector cytokines. The molecular control of IL-7Ra+ ILC development and maintenance has yet to be dissected. Here we report that GATA3 is indispensable for the development of all IL-7Ra+ ILC subsets and T cells. Gata3 conditional deficient mice have no lymph nodes and are susceptible to Citrobactor rodentium infection. Genome-wide gene analyses indicate that GATA3 regulates similar set of cytokines and receptors in ILC2s and Th2 cells and is critical for the maintenance of ILC2s. Thus, GATA3 plays parallel roles in establishing and regulating both adaptive and innate lymphocytes.
2014-03-13 | GSE47851 | GEO
Project description:Innate pattern recognition receptors for conserved structural elements play critical roles in immunity against viruses, bacteria and fungi, but analogous pathways linking innate recognition of diverse allergens or helminths with type 2 immunity remain elusive. The discovery of group 2 innate lymphoid cells (ILC2s), which produce similar cytokines as CD4+ T helper 2 (Th2) cells1, has suggested models whereby ILC2s directly or indirectly induce adaptive Th2 cells,2-8 but current understanding of how these cells interact in tissue microenvironments to coordinate allergic immunity is limited. Here, we show that tissue Th2 cells differentiate independently of ILC2s, but that both cell types share overlapping transcriptional and functional programs, which require exposure to the tissue-derived cytokines such as interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP). Combined loss of these epithelial cytokines affects neither Th2 cell priming nor T cell-dependent antibody production, but abrogates allergic lung inflammation due to requirements for local tissue signals to promote differentiation of effector function in both ILC2s and Th2 cells. Our findings reveal how diverse perturbations, including proteases, venoms and mechanical irritants, converge on common pathways to activate type 2 immune responses, thus uncovering a shared checkpoint that can be exploited to control both innate and adaptive allergic inflammation.
2016-10-17 | GSE79703 | GEO
Project description:Host defense against diverse pathogens involves the recruitment and differentiation of CD4+ T effector subsets including T helper 1 (Th1), Th2, Th17 and induced regulatory T (Treg) cells. Surface phenotype studies have revealed subset-specific surface markers for the identification and purification of human primary CD4+ T effector subsets. In the present study, we aimed to characterize the mRNA and large intergenic non-coding RNA (lincRNA) expression differences between human primary CD4+ T effector subsets and identify potential subset-specific genes. To achieve this goal, mRNA and lincRNA microarray profiling of flow cytometry-sorted human primary Th1, Th2, Th17 and Treg cells was performed. Principal component and pathway analyses revealed subset-specific gene expression patterns. A Th2-specific lincRNA, GATA3-AS1, also termed FLJ45983, was identified in primary immune cells and tissues, as well as in in vitro polarized CD4+ T effector subsets. Further analysis showed that GATA3-AS1 was a potential diagnostic marker in allergy, a Th2-associated disease. This first systematic genome-wide analysis of gene expression differences between primary CD4+ T effector subsets may help to identify novel regulatory protein-coding genes and lincRNAs regulating CD4+ T cell subset differentiation, as well as potential diagnostic markers. As an example, we identified a GATA3-associated Th2-specific marker lincRNA GATA3-AS1. Gene expression microarray analysis of flow-cytometry sorted human primary naïve CD4+ T cells, CD4+ T central memory cells, Th1, Th2, Th17 and Treg cells from buffy coat of four healthy controls Gene expression microarray analysis was performed using SurePrint G3 Human Gene Expression 8X60K microarray.
2013-06-01 | E-GEOD-43005 | biostudies-arrayexpress
Project description:Functionally polarized CD4+ T helper (Th) cells such as Th1, Th2 and Th17 cells are central to the regulation of acquired immunity. However, the molecular mechanisms governing the maintenance of the polarized functions of Th cells remain unclear. GATA3, a master regulator of Th2 cell differentiation, initiates the expressions of Th2 cytokine genes and other Th2-specific genes. GATA3 also plays important roles in maintaining Th2 cell function and in continuous chromatin remodeling of Th2 cytokine gene loci. However, it is unclear whether continuous expression of GATA3 is required to maintain the expression of various other Th2-specific genes. In this report, genome-wide DNA gene expression profiling revealed that GATA3 expression is critical for the expression of a certain set of Th2-specific genes. We demonstrated that GATA3 dependency is reduced for some Th2-specific genes in fully developed Th2 cells compared to that observed in effector Th2 cells, whereas it is unchanged for other genes. Moreover, effects of a loss of GATA3 expression in Th2 cells on the expression of cytokine and cytokine receptor genes were examined in detail. A critical role of GATA3 in the regulation of Th2-specific gene expression is confirmed in in vivo generated antigen-specific memory Th2 cells. Therefore, GATA3 is required for the continuous expression of the majority of Th2-specific genes involved in maintaining the Th2 cell identity. Mock-transfected and GATA3 siRNA-transfected Th2 and Th2-4th cells are profiled for mRNA expression
2013-04-19 | E-GEOD-46185 | biostudies-arrayexpress
Project description:Naïve CD4+ T-helper cells differentiate into Th2 effector cells during asthma and helminth (worm) infection. Here, we report that mice lacking the transcription factor Bcl11b in mature CD4+ T-cells are incapable of mounting an effective Th2 response in asthma and worm infection, with a major reduction of Th2 cytokine secretion and GATA3 expression. We found that Bcl11b exerts its role in Th2 differentiation through several avenues: (1) association with intronic regions at the Gata3 locus, sustaining GATA3 expression; (2) binding to and restricting chromatin accessibility at the Il4 silencer, located at hypersensitivity site (HS) IV; and (3) restricting Runx3 expression by association with a regulatory region 5’ of Runx3. Thus, in the absence of Bcl11b, the reduction in GATA3 levels combined with increased Runx3 levels and activity at Il4 HS IV silencer and consequently diminished IL-4 expression. This results in reduced chromatin opening at the Th2 locus control region (LCR), Il13 and Il5 promoters, subsequently preventing expression of Th2 cytokine genes and Th2 differentiation. Our results establish a novel role for Bcl11b in the regulatory loop critical for licensing the Th2 program in vivo.
2018-05-09 | GSE99598 | GEO
Project description:Naïve CD4+ T-helper cells differentiate into Th2 effector cells during asthma and helminth (worm) infection. Here, we report that mice lacking the transcription factor Bcl11b in mature CD4+ T-cells are incapable of mounting an effective Th2 response in asthma and worm infection, with a major reduction of Th2 cytokine secretion and GATA3 expression. We found that Bcl11b exerts its role in Th2 differentiation through several avenues: (1) association with intronic regions at the Gata3 locus, sustaining GATA3 expression; (2) binding to and restricting chromatin accessibility at the Il4 silencer, located at hypersensitivity site (HS) IV; and (3) restricting Runx3 expression by association with a regulatory region 5’ of Runx3. Thus, in the absence of Bcl11b, the reduction in GATA3 levels combined with increased Runx3 levels and activity at Il4 HS IV silencer and consequently diminished IL-4 expression. This results in reduced chromatin opening at the Th2 locus control region (LCR), Il13 and Il5 promoters, subsequently preventing expression of Th2 cytokine genes and Th2 differentiation. Our results establish a novel role for Bcl11b in the regulatory loop critical for licensing the Th2 program in vivo.
2018-05-09 | GSE99597 | GEO
Project description:Naïve CD4+ T-helper cells differentiate into Th2 effector cells during asthma and helminth (worm) infection. Here, we report that mice lacking the transcription factor Bcl11b in mature CD4+ T-cells are incapable of mounting an effective Th2 response in asthma and worm infection, with a major reduction of Th2 cytokine secretion and GATA3 expression. We found that Bcl11b exerts its role in Th2 differentiation through several avenues: (1) association with intronic regions at the Gata3 locus, sustaining GATA3 expression; (2) binding to and restricting chromatin accessibility at the Il4 silencer, located at hypersensitivity site (HS) IV; and (3) restricting Runx3 expression by association with a regulatory region 5’ of Runx3. Thus, in the absence of Bcl11b, the reduction in GATA3 levels combined with increased Runx3 levels and activity at Il4 HS IV silencer and consequently diminished IL-4 expression. This results in reduced chromatin opening at the Th2 locus control region (LCR), Il13 and Il5 promoters, subsequently preventing expression of Th2 cytokine genes and Th2 differentiation. Our results establish a novel role for Bcl11b in the regulatory loop critical for licensing the Th2 program in vivo.
2018-05-09 | GSE99595 | GEO
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
Project description:GATA3 is indispensable for the development of all IL-7Rα-expressing innate lymphoid cells (ILCs) and maintenance of type 1 ILCs (ILC1s) and type 2 ILCs (ILC2s). However, the importance of low GATA3 expression in type 3 ILCs (ILC3s) is still elusive. Here, we report that GATA3 regulates homeostasis of ILC3s by controlling IL-7Rα expression. In addition, GATA3 is critical for the development of NKp46+ ILC3 subset partially through regulating the balance between T-bet and RORγt. Genome-wide analyses indicate that while GATA3 positively regulates CCR6+ and NKp46+ ILC3 subset-specific genes in respective lineages, it negatively regulates CCR6+ ILC3-specific genes in NKp46+ ILC3s. Furthermore, GATA3 regulates IL-22 production in both CCR6+ and NKp46+ ILC3s. Thus, low GATA3 expression is critical for the development and function of ILC3 subsets. To identify GATA3 regulated genes in total ILC3s with RNA-Seq; To identify unique genes expressed by CCR6+ ILC3 or NKp46+ ILC3 and GATA3 regulated genes within these two ILC3 subsets with RNA-Seq; To identify GATA3 direct binding sites in ILC3s, ILC2s and Th2 cells with ChIP-Seq.
2015-11-23 | E-GEOD-71198 | biostudies-arrayexpress