Repression of the Transcription Factor Th-POK by Runx Complexes in Cytotoxic T Cell Development

Setoguchi, Ruka; Tachibana, Masashi; Naoe, Yoshinori; Muroi, Sawako; Akiyama, Kaori; Tezuka, Chieko; Okuda, Tsukasa; Taniuchi, Ichiro

doi:10.1126/science.1151844

Cited by 213 publications

(379 citation statements)

References 21 publications

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“…Thus, enhancer activity in the DRE has been supposed to be responsible for early Thpok induction. Interestingly, however, previous studies demonstrated that the DRE also possesses a transcriptional silencer activity that represses expression of reporter transgene as well as the Thpok gene in cytotoxic lineage cells (4,5). Thus, the silencer activity in the DRE (referred to as the Thpok silencer in this study) is essential to limit Thpok expression to helper lineage T cells.…”

mentioning

confidence: 83%

“…Preparation of chromatin DNA and primers for the PE were previously described (5). Abs used are control IgG (SC-2025) and anti-Gata3 (SC-268) from Santa Cruz Biotechnology.…”

Section: Chromatin Immunoprecipitation Assaymentioning

confidence: 99%

“…1A). An enhancer activity within the PRE, referred to as the proximal enhancer (PE), was shown to drive a reporter transgene in the later stage of helper lineage cell development (4,5). Alternatively, enhancer activity within the DRE was shown to drive reporter transgene expression mainly in CD4 + CD8 lo thymocytes (4).…”

mentioning

confidence: 99%

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Cutting Edge: Fine-Tuning of Thpok Gene Activation by an Enhancer in Close Proximity to Its Own Silencer

Muroi

Tanaka

Miyamoto

et al. 2013

The Journal of Immunology

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Differentiation of MHC class II–selected thymocytes toward the CD4+ helper lineage depends on function of the transcription factor ThPOK, whose expression is repressed in CD8+ cytotoxic lineage cells by a transcriptional silencer activity within the distal regulatory element (DRE) in the Thpok gene. Interestingly, the DRE also functions as a transcriptional enhancer. However, how the DRE exerts such dual functionality remains obscure. In this study, we dissected the DRE and identified DNA sequences specifically responsible for enhancer activity, and designated this as the thymic enhancer. Removal of the thymic enhancer from the murine Thpok locus resulted in inefficient ThPOK induction, thereby inducing a redirection toward alternative CD8+ cytotoxic lineage in a proportion of MHC class II–selected cells, even when they express monoclonal MHC class II–restricted transgenic TCR. Thus, regulation of contiguous but separable sequences with opposite function in the DRE plays an important role in precise coupling of TCR signaling with the selection process of two opposite lineages.

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mentioning

confidence: 83%

“…Preparation of chromatin DNA and primers for the PE were previously described (5). Abs used are control IgG (SC-2025) and anti-Gata3 (SC-268) from Santa Cruz Biotechnology.…”

Section: Chromatin Immunoprecipitation Assaymentioning

confidence: 99%

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Cutting Edge: Fine-Tuning of Thpok Gene Activation by an Enhancer in Close Proximity to Its Own Silencer

Muroi

Tanaka

Miyamoto

et al. 2013

The Journal of Immunology

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“…Altered T-cell phenotype in CD4-cre 1 Runx3 F/F , CD4-cre 1 ThPok F/F and CD4-cre 1 Runx3 F/F ThPok F/F mice The conventional T-cell fate model has indicated that ThPok is barely detectable in CD8 1 T cells, 22,38 and Runx3 expression in turn is decreased in CD4 1 T cells. 39,40 However, our real-time PCR analyses revealed that Runx3 and ThPok were both expressed in the CD4 1 and DN subsets of iNKT cells, whereas a low abundance of Runx1 mRNA was detected ( Figure 1a).…”

Section: Resultsmentioning

confidence: 99%

Runt-related transcription factor 3 is involved in the altered phenotype and function in ThPok-deficient invariant natural killer T cells

et al. 2014

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The interplay between the CD4-lineage transcription factor ThPok and the CD8-lineage transcription factor, runt-related transcription factor 3 (Runx3), in T-cell development has been extensively documented. However, little is known about the roles of these transcription factors in invariant natural killer T (iNKT) cell development. CD1d-restricted iNKT cells are committed to the CD4 1 CD8 2 and CD4 2 CD8 2 sublineages, which respond to antigen stimulation with rapid and potent release of T helper (Th) 1 and Th2 cytokines. However, previous reports have demonstrated a new population of CD8 1 NKT cells in ThPok-deficient mice. In the current study, we sought to determine whether Runx3 was involved in the re-expression of CD8 and function of iNKT cells in the absence of ThPok. We used mice lacking Runx3, ThPok or both and verified that Runx3 was partially responsible for the appearance of CD8 1 iNKT cells in ThPok knockout mice. Additionally, Runx3 participated in the immune response mediated by iNKT cells in a model of a-galactosylceramide-induced acute hepatitis. These results indicate that Runx3 is crucial for the phenotypic and functional changes observed in ThPok-deficient iNKT cells. and the canonical T-cell receptor a (TCRa) chain (Va14-Ja18 in mice and V24-J18 in humans) coupled to specific Vb chains (Vb8, Vb7 and Vb2 in mice and Vb11 in humans). These receptors are responsible for the interaction of NKT cells with CD1d molecules expressed on CD4 1 CD8 1 double-positive (DP) thymocytes. 1 NKT cells are classified into type I (defined as invariant (iNKT) or classical NKT cells) and type II based on the antigens recognized by each and their TCR repertoires. 2 Our study focused on type I NKT cells (hereafter referred to as iNKT cells). iNKT cells recognize the glycosphingolipid antigen a-galactosylceramide (a-GalCer) and a-GalCer loading with the tetrameric form of CD1d is often used to define the iNKT cell subset because of the high affinity of CD1d for the iNKT cell TCR. 3 Although iNKT cells originate from CD4 1 CD8 1 (DP) thymocytes 4 and are selected by MHC class

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“…Previous research has revealed that transcription factors c-Myb, Gata3, Tox, and cKrox (also known as Thpok or Zbtb7b) act as CD4 lineage-specifying factors [6][7][8][9][10][11][12][13], whereas Runx3 is required for CD8 lineage differentiation [14,15]. Runx3 has dual functions during CD8 lineage differentiation, where it can act as a repressor by binding to the cis-regulatory silencer elements of the Cd4 and Zbtb7b gene locus and as an activator by promoting CD8 lineage-related gene expression [15][16][17][18]. However, the mechanisms by which these lineage-specifying factors are regulated remain largely unknown.…”

Section: Cd8mentioning

confidence: 99%

Interferon regulatory factor 4 regulates thymocyte differentiation by repressing Runx3 expression

Cao

Sun

et al. 2010

Eur J Immunol

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The transcription factor interferon regulatory factor 4 (IRF4) was originally found to be preferentially expressed in lymphoid cells and to be required for the function, differentiation, and homeostasis of both mature T and B lymphocytes. Recent studies have indicated that IRF4 is also involved in early B-cell development. However, the role of IRF4 in intrathymic T-cell development remains unknown. In this study, we show that IRF4 is upregulated in TCR-signaled thymocytes and is predominantly expressed in CD4 singlepositive (SP), but not in CD8 SP, cells. T-cell-specific overexpression of IRF4 impaired the generation and maturation of CD8 SP thymocytes. Further analysis revealed that IRF4 selectively bound to the distal promoter region of Runx3 and repressed its transcription, probably through the deacetylation of histones H3 and H4 in intermediate CD4 [1][2][3]. This process is accompanied by new gene expression programs. One apparent change that occurs is the silencing of CD4 or CD8 expression in DP thymocytes [4,5]. Previous research has revealed that transcription factors c-Myb, Gata3, Tox, and cKrox (also known as Thpok or Zbtb7b) act as CD4 lineage-specifying factors [6][7][8][9][10][11][12][13], whereas Runx3 is required for CD8 lineage differentiation [14,15]. Runx3 has dual functions during CD8 lineage differentiation, where it can act as a repressor by binding to the cis-regulatory silencer elements of the Cd4 and Zbtb7b gene locus and as an activator by promoting CD8 lineage-related gene expression [15][16][17][18]. However, the mechanisms by which these lineage-specifying factors are regulated remain largely unknown.Interferon regulatory factor (IRF) family members are transcription factors that are composed of a DNA-binding domain and a regulatory domain that regulate a series of immune-related Ã These authors have contributed equally to this work. 3198genes [19,20]. The functions of IRF include a number of distinct roles in biological processes, such as pathogen response, cytokine signaling, cell growth regulation, and hematopoietic development [19,20]. IRF4 (also known as Pip, ICSAT, or LSIRF) is a lymphocyte-restricted member of the IRF family of transcription factors that bind to the interferon-stimulated response element (ISRE; consensus sequence: A / G NGAAANNGAAACT) and interferon-g-activated sequence element (GAS; consensus sequence: TTTNCNNNAA) [19,[21][22][23]. IRF4 can act as either a transcriptional activator or a repressor, which is determined by the DNAbinding motif on specific promoters as well as interaction with distinct transcription factors [22]. IRF4 is not only critical for lymphocyte maturation, homeostasis, and differentiation, including Th2, Th17, and B-lymphocyte differentiation, but is also important for cytotoxic, antitumor, and humoral responses [19,20,[24][25][26]. As a transcription factor, IRF4 is required for early B-cell development and regulates a series of B-cell-specific genes in activated B cells and myeloma, such as the immunoglobulin light chain gene [19,27]....

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Repression of the Transcription Factor Th-POK by Runx Complexes in Cytotoxic T Cell Development

Cited by 213 publications

References 21 publications

Cutting Edge: Fine-Tuning of Thpok Gene Activation by an Enhancer in Close Proximity to Its Own Silencer

Cutting Edge: Fine-Tuning of Thpok Gene Activation by an Enhancer in Close Proximity to Its Own Silencer

Runt-related transcription factor 3 is involved in the altered phenotype and function in ThPok-deficient invariant natural killer T cells

Interferon regulatory factor 4 regulates thymocyte differentiation by repressing Runx3 expression

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