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Bcl11b, a Novel GATA3-Interacting Protein, Suppresses Th1 while Limiting Th2 Cell Differentiation (H3K27ac and DNase-Seq)

ABSTRACT: GATA-binding protein 3 (GATA3) acts as the master transcription factor for type 2 T helper (Th2) cell differentiation and function. However, it is still elusive how GATA3 function is precisely regulated in Th2 cells. Here, we report that the transcription factor B cell lymphoma 11b (Bcl11b), a previously unknown component of GATA3 transcriptional complex, is involved in GATA3-mediated gene regulation. Bcl11b binds to GATA3 through protein-protein interaction, and they co-localize at many important cis-regulatory elements in Th2 cells. The expression of type 2 cytokines, including IL-4, IL-5 and IL-13, is up-regulated in Bcl11b-deficient Th2 cells both in vitro and in vivo; such up-regulation is completely GATA3-dependent. Genome-wide analyses of Bcl11b- and GATA3-regulated gene (from RNA-Seq), co-binding pattern (from ChIP-Seq), and Bcl11b-mediated epigenetic changes (in H3K27ac and DHSs) suggest that GATA3/Bcl11b complex is involved in limiting Th2 gene expression, as well as in inhibiting non-Th2 gene expression. Thus, Bcl11b controls both GATA3-mediated gene activation and repression in Th2 cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE108633 | GEO | 2018/03/05

REPOSITORIES: GEO

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Bcl11b- and GATA3-mediated gene regulation in Th2 cells

Project description:GATA-binding protein 3 (GATA3) acts as the master transcription factor for type 2 T helper (Th2) cell differentiation and function. However, it is still elusive how GATA3 function is precisely regulated in Th2 cells. Here, we report that the transcription factor B cell lymphoma 11b (Bcl11b), a previously unknown component of GATA3 transcriptional complex, is involved in GATA3-mediated gene regulation. Bcl11b binds to GATA3 through protein-protein interaction, and they co-localize at many important cis-regulatory elements in Th2 cells. The expression of type 2 cytokines, including IL-4, IL-5 and IL-13, is up-regulated in Bcl11b-deficient Th2 cells both in vitro and in vivo; such up-regulation is completely GATA3-dependent. Genome-wide analyses of Bcl11b- and GATA3-regulated gene (from RNA-Seq), co-binding pattern (from ChIP-Seq), and Bcl11b-mediated epigenetic changes (in H3K27ac and DHSs) suggest that GATA3/Bcl11b complex is involved in limiting Th2 gene expression, as well as in inhibiting non-Th2 gene expression. Thus, Bcl11b controls both GATA3-mediated gene activation and repression in Th2 cells.

2018-03-05 | GSE109107 | GEO

Project description:Bcl11b- and GATA3-mediated gene regulation in Th2 cells

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Mapping of Bcl11b binding in CD4+ T-cells during Th2 immune response

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.

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Genome wide mapping of accessible chromatin in CD4+ T-cells during Th2 immune responses

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Transcriptome analysis of Bcl11b-deficient CD4+ T-cells during Th2 immune response

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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 transcription factor GATA3 is critical for the development of all IL-7Ra-expressing innate lymphoid cells (ILCs) and maintenance of type 2 ILCs

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2014-03-13 | E-GEOD-47851 | biostudies-arrayexpress

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Group 3 innate lymphoid cells continuously require the transcription factor GATA3 after commitment

Project description:GATA3 is indispensable for the development of all IL-7RÎ±-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-7RÎ± expression. In addition, GATA3 is critical for the development of NKp46+ ILC3 subset partially through regulating the balance between T-bet and RORÎ³t. 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

Genome-wide identification of Bcl11b gene targets

Project description:B-cell leukemia/lymphoma 11B (Bcl11b) is a transcription factor showing predominant expression in the striatum. To date, there are no known gene targets of Bcl11b in the nervous system. Here, we define targets for Bcl11b in striatal cells by performing genome-wide expression profiling. Transcriptome-wide analysis revealed that 694 genes were significantly altered in striatal cells over-expressing Bcl11b, including genes showing striatal-enriched expression similar to Bcl11b. Functional analysis on the gene target list identified significant association of Bcl11b to brain-derived neurotrophic factor/neurotrophin signaling. These data implicate Bcl11b as a novel regulator of the BDNF signaling pathway, which is disrupted in many neurological disorders. n=4 wt STHdh striatal cells and n=4 Bcl11b-transfected STHdh striatal cells

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