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

Muroi, Sawako; Tanaka, Hirokazu; Miyamoto, Chizuko; Taniuchi, Ichiro

doi:10.4049/jimmunol.1203006

Cited by 17 publications

(21 citation statements)

References 15 publications

(15 reference statements)

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“…). While removal of the TE from a Thpok gfp reporter allele attenuated GFP reporter expression only in freshly selected thymocytes , removal of the PE impaired GFP expression after the later maturation stage . These observations indicate stage‐specific, as well as redundant, activity between TE and PE.…”

Section: Positive Regulation Of the Thpok Genementioning

confidence: 82%

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Views on helper/cytotoxic lineage choice from a bottom‐up approach

Taniuchi

2016

Immunological Reviews

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There has been speculation as to how bi-potent CD4(+) CD8(+) double-positive precursor thymocytes choose their distinct developmental fate, becoming either CD4(+) helper or CD8(+) cytotoxic T cells. Based on the clear correlation of αβT cell receptor (TCR) specificity to major histocompatibility complex (MHC) classes with this lineage choice, various studies have attempted to resolve this question by examining the cellular signaling events initiated by TCR engagements, a strategy referred to as a 'top-down' approach. On the other hand, based on the other correlation of CD4/CD8 co-receptor expression with its selected fate, other studies have addressed this question by gradually unraveling the sequential mechanisms that control the phenotypic outcome of this fate decision, a method known as the 'bottom-up' approach. Bridging these two approaches will contribute to a more comprehensive understanding of how TCR signals are coupled with developmental programs in the nucleus. Advances made during the last two decades seemed to make these two approaches more closely linked. For instance, identification of two transcription factors, ThPOK and Runx3, which play central roles in the development of helper and cytotoxic lineages, respectively, provided significant insights into the transcriptional network that controls a CD4/CD8 lineage choice. This review summarizes achievements made using the 'bottom-up' approach, followed by a perspective on future pathways toward coupling TCR signaling with nuclear programs.

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Section: Positive Regulation Of the Thpok Genementioning

confidence: 82%

“…Later, it was apparent that distinct sequences within DRE were responsible for respective activities. Thus, the regions responsible for enhancer and silencer activity are designated as the ‘thymic enhancer’ and the ‘ Thpok silencer’, respectively ( Fig. ).…”

Section: Runx Encounters Thpok: Proof For Of the Correct Direction Inmentioning

confidence: 99%

Views on helper/cytotoxic lineage choice from a bottom‐up approach

Taniuchi

2016

Immunological Reviews

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“…Hence additional mechanisms must exist that at least in part integrate the combined activity of MAZR and Runx1 for the appropriate repression of the Thpok gene. The Thpok thymic enhancer and PE were shown to be required for the initial induction of Thpok in MHC class II-selected DP thymocytes (7,10). It might therefore be possible that MAZR and Runx/ CBFb complexes negatively regulate thymic enhancer and/or PE activity in DP thymocytes, and that the combined repressive activity of MAZR and Runx/CBFb complexes is overcome when DP thymocytes receive MHC class II signals during CD4 lineage differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…Another essential cis-regulatory element, designated as Thpok silencer, is located ∼3 kb upstream of exon 1A and represses ThPOK expression during CD8 lineage differentiation and in peripheral CD8 + T cells (8,9). Although PE and the Thpok silencer are the key regulatory elements required for the lineage-specific expression of ThPOK, studies indicate the presence of additional cis-regulatory elements (9,10).…”

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confidence: 99%

MAZR and Runx Factors Synergistically Repress ThPOK during CD8+ T Cell Lineage Development

Sakaguchi

Hainberger

Tizian

et al. 2015

The Journal of Immunology

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Th-inducing Pox virus and zinc finger/Krüppel-like factor (ThPOK) is a key commitment factor for CD4+ lineage T cells and is essential for the maintenance of CD4 lineage integrity; thus, the expression of ThPOK has to be tightly controlled. In this article, we demonstrate that Myc-associated zinc finger-related factor (MAZR) and Runt-related transcription factor 1 (Runx1) together repressed ThPOK in preselection double-positive thymocytes, whereas MAZR acted in synergy with Runx3 in the repression of ThPOK in CD8+ T cells. Furthermore, MAZR-Runx1 and MAZR-Runx3 double-mutant mice showed enhanced derepression of Cd4 in double-negative thymocytes and in CD8+ T cells in comparison with Runx1 or Runx3 single-deficient mice, respectively, indicating that MAZR modulates Cd4 silencing. Thus, our data demonstrate developmental stage-specific synergistic activities between MAZR and Runx/core-binding factor β (CBFβ) complexes. Finally, retroviral Cre-mediated conditional deletion of MAZR in peripheral CD8+ T cells led to the derepression of ThPOK, thus showing that MAZR is also part of the molecular machinery that maintains a repressed state of ThPOK in CD8+ T cells.

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“…TCRβ + DP and IM thymocytes (Figure 21E). To investigate Thpok transcriptional activity, we crossed the Tcf7 −/− or Tcf7 −/− Lef1 −/− mice with a knock-in Thpok GFP reporter gene 131 . We analyzed the immature subsets from Tcf7 −/− or Tcf7 −/− Lef1 −/− mice containing the Thpok GFP knock-in gene (Figure 22A).…”

Section: Tcf-1 Deficiency Substantially Diminished the Expression Of mentioning

confidence: 99%

Novel roles for TCF-1 and LEF-1 in directing CD4+ T cell fate and silencing CD4 in CD8+ T cells

Steinke¹

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I would like to thank the University of Iowa Flow Cytometry Facility and its engineers, Justin Fishbaugh, Heath Vignes and George Rasmussen for their cordial and knowledgeable support of my research. They always performed their work humbly, yet flawlessly and exhibited a professionalism matched only by their compassion. Thank you for your patience and help over the years.I need to thank all who have guided and supported me from the beginnings of my passion for science, including those who have unknowingly made me a dedicated scientist. To all of my friends, including the golden oldies, the new colleagues who've formed summer softball teams and social outings in Iowa City, and various teammates from tennis club and Trihawks, thanks for being an understanding and wholesome outlet.To the middle school science teachers, the variety of coaches and especially the family members who have always encouraged the pursuit of knowledge and happiness -thank you.v ABSTRACT CD4 + and CD8 + T cells, the essential mediators of cellular immune responses, are produced in the thymus following sequential maturation stages. Hematopoietic progenitors first seed the thymus and make T cell lineage specification and commitment decisions within the CD4 − CD8 − double negative (DN) compartment. Thymocytes then mature to the CD4 + CD8 + double positive (DP) stage, followed by vigorous negative and positive selection processes. The positively selected DP thymocytes first give rise to CD4 + CD8 lo intermediate (IM) cells which then differentiate into MHC class II-restricted CD4 + and MHC class I-restricted CD8 + T cells, a crucial decision known as CD4 + vs.The lineage choice decision is influenced by the timing, intensity, and duration of signals derived from the TCR and cytokines, and recent studies have identified a number of transcriptional factors that intrinsically regulate this critical fate decision. Among these, Th-POK (encoded by Zbtb7b, called Thpok here for simplicity and consistency with the literature) is specifically required for CD4 + differentiation while Runx factors promote CD8 + T cell production and repress Cd4 in CD8 + lineage committed cells.Upregulation of Thpok is most evident in the CD4 + 8 lo IM cells and is required to antagonize Runx3 activity and expression to promote CD4 + lineage commitment.Collectively, the Th-POK-Runx3 axis appears to be a critical convergence point in the CD4 + vs. CD8 + lineage choice.After committing to either CD4 + or CD8 + thymocytes, lineage-inappropriate genes are silenced to ensure the distinct identity and functional divergence between these two cell types. Repression of the Cd4 gene on CD8 + lineage committed cells is mediated vi by a ~430 bp silencer sequence in its first intron. Likewise, Thpok is repressed in CD8 + T cells by a ~560 bp sequence upstream of the Thpok exon 1a, and both Cd4 and Thpok silencers contain consensus binding motifs for Runx factors, which are necessary for CD8 + lineage commitment.T cell factor 1 (TCF-1) and lymphoid enhancer binding factor 1 (LEF-1) are me...

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

Cited by 17 publications

References 15 publications

Views on helper/cytotoxic lineage choice from a bottom‐up approach

Views on helper/cytotoxic lineage choice from a bottom‐up approach

MAZR and Runx Factors Synergistically Repress ThPOK during CD8+ T Cell Lineage Development

Novel roles for TCF-1 and LEF-1 in directing CD4+ T cell fate and silencing CD4 in CD8+ T cells

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