STAT6-mediated displacement of polycomb by trithorax complex establishes long-term maintenance of GATA3 expression in T helper type 2 cells

Onodera, Atsushi; Yamashita, Masakatsu; Endo, Yusuke; Kuwahara, Makoto; Tofukuji, Soichi; Hosokawa, Hiroyuki; Kanai, Akinori; Suzuki, Yutaka; Nakayama, Toshinori

doi:10.1084/jem.20100760

Cited by 88 publications

(134 citation statements)

References 51 publications

(61 reference statements)

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“…In in vitro Th1/Th2 cultures, Th1 and Th2 cell differentiation of Menin −/− T cells were not impaired as evidenced by IFN-γ and IL-4 production, respectively ( Fig. S1 A and B) (23). In contrast, a dramatic reduction in the number of IL-17A-producing cells was observed in Menin −/− Th17 cell cultures (Fig.…”

Section: Resultsmentioning

confidence: 85%

“…Menin is an essential component of the MLL/TrxG complex that is required for DNA binding (25). In the context of Th2 cells, we have reported that Menin is crucial for the maintenance of Gata3 expression and the function of Th2 cells after differentiation (23). However, it remains unclear whether the Menin/TrxG complex is involved in the differentiation or maintenance of function of Th17 cells.…”

Section: Resultsmentioning

confidence: 99%

“…We have previously shown that, once Th2 cell differentiation takes place, Gata3 expression and Th2 function is maintained via recruitment of the Menin/TrxG complex to the Gata3 gene locus, even in the absence of IL-4-mediated STAT6 activation (23). We examined whether the expression of Rorc is maintained in a similar fashion via the binding of the Menin/TrxG complex in an IL-6/STAT3-independent manner.…”

Section: Menin Is Crucial For Maintaining the Expression Of Rorc And mentioning

confidence: 99%

“…Menin is a highly specific partner for MLL proteins and is an essential component required for DNA binding of the TrxG/MLL complex (22). The binding of the Menin/TrxG complex is required for the maintenance of Gata3 expression and Th2 cytokine production in established Th2 cells (23), and the same mechanism was also recently found to function in human Th2 cells (24). However, it remains unclear whether the Menin/TrxG complex is involved in the differentiation and maintenance of other Th cell subsets.…”

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confidence: 99%

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Trithorax complex component Menin controls differentiation and maintenance of T helper 17 cells

Watanabe¹,

Onodera²,

Kanai³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Epigenetic modifications, such as posttranslational modifications of histones, play an important role in gene expression and regulation. These modifications are in part mediated by the Trithorax group (TrxG) complex and the Polycomb group (PcG) complex, which activate and repress transcription, respectively. We herein investigate the role of Menin, a component of the TrxG complex in T helper (Th) cell differentiation and show a critical role for Menin in differentiation and maintenance of Th17 cells. Menin −/− T cells do not efficiently differentiate into Th17 cells, leaving Th1 and Th2 cell differentiation intact in in vitro cultures. Menin deficiency resulted in the attenuation of Th17-induced airway inflammation. In differentiating Th17 cells, Menin directly bound to the Il17a gene locus and was required for the deposition of permissive histone modifications and recruitment of the RNA polymerase II transcriptional complex. Interestingly, although Menin bound to the Rorc locus, Menin was dispensable for the induction of Rorc expression and permissive histone modifications in differentiating Th17 cells. In contrast, Menin was required to maintain expression of Rorc in differentiated Th17 cells, indicating that Menin is essential to stabilize expression of the Rorc gene. Thus, Menin orchestrates Th17 cell differentiation and function by regulating both the induction and maintenance of target gene expression.

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Section: Resultsmentioning

confidence: 85%

Section: Resultsmentioning

confidence: 99%

Section: Menin Is Crucial For Maintaining the Expression Of Rorc And mentioning

confidence: 99%

mentioning

confidence: 99%

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Trithorax complex component Menin controls differentiation and maintenance of T helper 17 cells

Watanabe¹,

Onodera²,

Kanai³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…After antigenic stimulation in a particular cytokine milieu, naïve CD4 T cells differentiate into one of several Th cell subsets including Th1 and Th2 cells (6). Differentiation of Th2 cells requires IL-4 stimulation, which leads to Stat6 phosphorylation and the up-regulation of Gata3 transcription (7,8). The deletion of Gata3 in peripheral CD4 T cells prevents their differentiation into the Th2 lineage, causing cells to differentiate toward a Th1 phenotype in the absence of polarizing cytokines (9,10).…”

Section: T Helper 2 Cell Differentiation | Transcriptional Regulationmentioning

confidence: 99%

Functionally distinct Gata3/Chd4 complexes coordinately establish T helper 2 (Th2) cell identity

Hosokawa¹,

Tanaka

Suzuki

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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GATA binding protein 3 (Gata3) is a GATA family transcription factor that controls differentiation of naïve CD4 T cells into T helper 2 (Th2) cells. However, it is unknown how Gata3 simultaneously activates Th2-specific genes while repressing those of other Th lineages. Here we show that chromodomain helicase DNA-binding protein 4 (Chd4) forms a complex with Gata3 in Th2 cells that both activates Th2 cytokine transcription and represses the Th1 cytokine IFN-γ. We define a Gata3/Chd4/p300 transcriptional activation complex at the Th2 cytokine loci and a Gata3/Chd4–nucleosome remodeling histone deacetylase repression complex at the Tbx21 locus in Th2 cells. We also demonstrate a physiological role for Chd4 in Th2-dependent inflammation in an in vivo model of asthmatic inflammation. Thus, Gata3/Chd4 forms functionally distinct complexes, which mediate both positive and negative gene regulation to facilitate Th2 cell differentiation.

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Chromatin priming elements establish immunological memory in T cells without activating transcription

2016

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We have identified a simple epigenetic mechanism underlying the establishment and maintenance of immunological memory in T cells. By studying the transcriptional regulation of inducible genes we found that a single cycle of activation of inducible factors is sufficient to initiate stable binding of pre-existing transcription factors to thousands of newly activated distal regulatory elements within inducible genes. These events lead to the creation of islands of active chromatin encompassing nearby enhancers, thereby supporting the accelerated activation of inducible genes, without changing steady state levels of transcription in memory T cells. These studies also highlighted the need for more sophisticated definitions of gene regulatory elements. The chromatin priming elements defined here are distinct from classical enhancers because they function by maintaining chromatin accessibility rather than directly activating transcription. We propose that these priming elements are members of a wider class of genomic elements that support correct developmentally regulated gene expression.

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STAT6-mediated displacement of polycomb by trithorax complex establishes long-term maintenance of GATA3 expression in T helper type 2 cells

Abstract: Trithorax group complex is needed for initiation as well as maintenance of GATA3 gene expression in Th2 cells.

Cited by 88 publications

References 51 publications

Trithorax complex component Menin controls differentiation and maintenance of T helper 17 cells

Trithorax complex component Menin controls differentiation and maintenance of T helper 17 cells

Functionally distinct Gata3/Chd4 complexes coordinately establish T helper 2 (Th2) cell identity

Chromatin priming elements establish immunological memory in T cells without activating transcription

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