Regulation of Th2 Cell Development by <i>Polycomb</i> Group Gene <i>bmi-1</i> through the Stabilization of GATA3

Hosokawa, Hiroyuki; Kimura, Motoko; Shinnakasu, Ryo; Suzuki, Akane; Miki, Takako; Koseki, Haruhiko; Lohuizen, Maarten van; Yamashita, Masakatsu; Nakayama, Toshinori

doi:10.4049/jimmunol.177.11.7656

Cited by 53 publications

(54 citation statements)

References 57 publications

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“…2D, 2E). This result is similar to that of Bmi-1-deficient Th2 cells (44). Therefore, Ring1B may cooperate with Bmi-1 to control the stability of GATA3 protein and facilitate Th2 cell differentiation.…”

Section: Discussionsupporting

confidence: 73%

“…We previously reported that Mel-18 and Bmi-1 controls Th2 cell differentiation through distinct mechanisms; namely, Mel-18 regulates GATA3 transcription, and Bmi-1 regulates the stability of GATA3 protein (43,44). In this paper, we show that another PcG molecule, Ring1B, plays a role in Th2 cell differentiation.…”

Section: Discussionmentioning

confidence: 60%

“…In mature lymphocytes, PcG gene products play several roles in the differentiation process and cell fate. Mel-18 controls Th2 cell differentiation through the regulation of GATA3 expression (43), and Bmi-1 controls the stability of GTAT3 protein in developing Th2 cells (44). Moreover, Bmi-1 controls memory CD4 T cell survival through the direct repression of the Noxa gene (45).…”

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confidence: 99%

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Polycomb Group Gene Product Ring1B Regulates Th2-Driven Airway Inflammation through the Inhibition of Bim-Mediated Apoptosis of Effector Th2 Cells in the Lung

Suzuki

Iwamura

Shinoda

et al. 2010

The Journal of Immunology

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Polycomb group (PcG) gene products regulate the maintenance of homeobox gene expression in Drosophila and vertebrates. In the immune system, PcG molecules control cell cycle progression of thymocytes, Th2 cell differentiation, and the generation of memory CD4 T cells. In this paper, we extended the study of PcG molecules to the regulation of in vivo Th2 responses, especially allergic airway inflammation, by using conditional Ring1B-deficient mice with a CD4 T cell-specific deletion of the Ring1B gene (Ring1B−/− mice). In Ring1B−/− mice, CD4 T cell development appeared to be normal, whereas the differentiation of Th2 cells but not Th1 cells was moderately impaired. In an Ag-induced Th2-driven allergic airway inflammation model, eosinophilic inflammation was attenuated in Ring1B−/− mice. Interestingly, Ring1B−/− effector Th2 cells were highly susceptible to apoptosis in comparison with wild-type effector Th2 cells in vivo and in vitro. The in vitro experiments revealed that the expression of Bim was increased at both the transcriptional and protein levels in Ring1B−/− effector Th2 cells, and the enhanced apoptosis in Ring1B−/− Th2 cells was rescued by the knockdown of Bim but not the other proapoptotic genes, such as Perp, Noxa, or Bax. The enhanced apoptosis detected in the transferred Ring1B−/− Th2 cells in the lung of the recipient mice was also rescued by knockdown of Bim. Therefore, these results indicate that Ring1B plays an important role in Th2-driven allergic airway inflammation through the control of Bim-dependent apoptosis of effector Th2 cells in vivo.

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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 60%

mentioning

confidence: 99%

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Polycomb Group Gene Product Ring1B Regulates Th2-Driven Airway Inflammation through the Inhibition of Bim-Mediated Apoptosis of Effector Th2 Cells in the Lung

Suzuki

Iwamura

Shinoda

et al. 2010

The Journal of Immunology

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“…In peripheral CD4 T cells, the activation of STAT6 induces highlevel GATA3 mRNA expression (12), and we and others have recently reported that STAT6 binds to specific regions of the GATA3 gene to regulate its transcription (13,14). In addition, the protein expression of GATA3 in Th2 cells is regulated by various posttranscriptional mechanisms (15)(16)(17). Changes in histone modifications, such as H3-K9/14 acetylation and H3-K4 methylation at the Th2 cytokine gene loci, occur during Th2 cell differentiation (18)(19)(20), and this is induced primarily by GATA3 in both CD4 and CD8 T cells (21).…”

mentioning

confidence: 99%

Genome-Wide Analysis Reveals Unique Regulation of Transcription of Th2-Specific Genes by GATA3

Horiuchi

Onodera

Hosokawa

et al. 2011

The Journal of Immunology

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Differentiation of naive CD4 T cells into 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 chromatin immunoprecipitation assay coupled with massive parallel sequencing analysis revealed that GATA3 bound to 1279 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 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, whereas 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.

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“…Enforced expression of GATA3 has also been reported to endogenously upregulate GATA3 expression [36]. In addition, the amount of GATA3 protein in Th2 cells is regulated by various postranscriptional mechanisms [37][38][39]. Furthermore, high-level expression of GATA3 is essential for the production of large amounts of Th2 cytokines in established Th2 cells [11,[40][41][42].…”

Section: Gata3 Plays Roles In Various Tissues As Well As the Immune Smentioning

confidence: 99%

The Interplay between Transcription Factors and Epigenetic Modifications in Th2 Cells

Onodera¹,

Kokubo²,

Nakayama³

2018

Gene Expression and Regulation in Mammalian Cells - Transcription From General Aspects

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Functionally polarized CD4 T helper (Th) cells, such as Th1, Th2, and Th17 cells, are essential for the regulation of acquired immunity. Diferentiation of naïve CD4 T cells into Th2 cells is characterized by chromatin remodeling and the induced expression of a set of Th2-speciic genes, which include Th2 cytokine genes. In the irst stage of this differentiation, a Th2-skewing cytokine environment, especially IL-4, induces STAT6 activation. Activated STAT6 increases the expression of GATA3, a master regulator of Th2 cell diferentiation, via direct binding to the Gata3 gene locus. This transcriptional induction of Gata3 mRNA during Th2 cell diferentiation is accompanied by dynamic changes in the binding paterns of two epigenetic modiication proteins such as Polycomb and Trithorax complexes. Consequently, expressed GATA3 epigenetically modiies and upregulates Th2-speciic genes to establish Th2 cell identity. This identity is maintained by high-level expression of the Gata3 gene controlled by Menin, which is a member of the Trithorax proteins, after cycles of cultivation in vitro and a long-term resting state in vivo. Thus, the Menin-GATA3 axis handles the Th2-speciic gene regulatory network.

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Regulation of Th2 Cell Development by Polycomb Group Gene bmi-1 through the Stabilization of GATA3

Cited by 53 publications

References 57 publications

Polycomb Group Gene Product Ring1B Regulates Th2-Driven Airway Inflammation through the Inhibition of Bim-Mediated Apoptosis of Effector Th2 Cells in the Lung

Polycomb Group Gene Product Ring1B Regulates Th2-Driven Airway Inflammation through the Inhibition of Bim-Mediated Apoptosis of Effector Th2 Cells in the Lung

Genome-Wide Analysis Reveals Unique Regulation of Transcription of Th2-Specific Genes by GATA3

The Interplay between Transcription Factors and Epigenetic Modifications in Th2 Cells

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