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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE99595 | GEO | 2018/05/09

REPOSITORIES: GEO

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Transcriptome analysis of Bcl11b-deficient 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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Project description:Bcl11b- and GATA3-mediated gene regulation in Th2 cells

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The transcription factor Zfp281 serves redundantly with Zfp148 to support CD4+ T cell development and functions [Th2 ChIP]

Project description:The transcription factor Gata3 is essential both for CD4+ T cell development in the thymus and for the differentiation of Th2 cells, which mediate responses against extracellular parasites and contribute to asthma and allergies. Here we report that the transcription factor Zfp281, in part redundantly with its paralog Zfp148, cooperates with Gata3 to promote CD4+ T cell development and Th2 cell differentiation. Disruption of both factors in T cells resulted in reduced numbers of spleen CD4+ T cells. Additionally, we show that Zfp281 interacts with Gata3, and that Zfp281 binds to Th2 cytokine loci in Th2 cells. Finally, we found that Zfp148 and Zfp281 promote Th2 cytokine expression. During airway inflammation, Zfp148/281-deficient CD4+ T cells failed to express Th2 cytokines, despite normal expression of Gata3. Altogether our data identify Zfp148 and Zfp281 as essential for enabling Gata3 functions in both CD4+ T cell development and Th2 function.

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