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

Sakaguchi, Shoji; Hainberger, Daniela; Tizian, Caroline; Tanaka, Hirokazu; Okuda, Tsukasa; Taniuchi, Ichiro; Ellmeier, Wilfried

doi:10.4049/jimmunol.1500387

Cited by 26 publications

(43 citation statements)

References 33 publications

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“…). Recently, synergic functions of MAZR and Runx in repressing Thpok and Cd4 genes was reported , further confirming that these two proteins could form functional complexes on these silencers. It was also reported that Bcl11b transcription factor is involved in Thpok repression in precursor DP thymocytes , as the Thpok gene is de‐repressed from those cells upon inactivation of the Bcl11b gene by the Cd4‐Cre transgene.…”

Section: Thpok Silencer: the Right Place To Meet Tcr Signals In The Bmentioning

confidence: 70%

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: Thpok Silencer: the Right Place To Meet Tcr Signals In The Bmentioning

confidence: 70%

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

Taniuchi

2016

Immunological Reviews

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“…Among them, the thymic enhancer ( TE ), located upstream of the Sth , acts first to initiate Thpok expression 21 , which is subsequently upregulated through the activity of a proximal enhancer ( PE ) locating 1.8 kb downstream of the proximal P2-promoter 22 . While factors that regulate Sth activity, such as Runx family proteins 19 and MAZR 23 , 24 , have been identified, the factors involved in the activation of TE and PE remain poorly characterized. Gata3 25 and Tcf1/Lef1 26 regulate Thpok expression, but primarily do so by targeting other regulatory regions such as general T-lymphoid enhancer, the known third enhancer.…”

Section: Introductionmentioning

confidence: 99%

Priming of lineage-specifying genes by Bcl11b is required for lineage choice in post-selection thymocytes

et al. 2017

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T-lineage committed precursor thymocytes are screened by a fate-determination process mediated via T cell receptor (TCR) signals for differentiation into distinct lineages. However, it remains unclear whether any antecedent event is required to couple TCR signals with the transcriptional program governing lineage decisions. Here we show that Bcl11b, known as a T-lineage commitment factor, is essential for proper expression of ThPOK and Runx3, central regulators for the CD4-helper/CD8-cytotoxic lineage choice. Loss of Bcl11b results in random expression of these factors and, thereby, lineage scrambling that is disconnected from TCR restriction by MHC. Initial Thpok repression by Bcl11b prior to the pre-selection stage is independent of a known silencer for Thpok, and requires the last zinc-finger motif in Bcl11b protein, which by contrast is dispensable for T-lineage commitment. Collectively, our findings shed new light on the function of Bcl11b in priming lineage-specifying genes to integrate TCR signals into subsequent transcriptional regulatory mechanisms.

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“…In the absence of Mazr, Thpok was derepressed in DP thymocytes, leading to lineage redirection of MHC class I selected thymocytes into the helper lineage. The derepression of Thpok was enhanced when combined with mutations in Runx1 or Runx3 (131). CD4 derepression was also enhanced in DN thymocytes doubly deficient for Runx proteins and Mazr, supporting a cooperative role between these factors (131).…”

Section: Cis Elements and Epigenetic Regulation Of The Cd8 Locusmentioning

confidence: 99%

“…The derepression of Thpok was enhanced when combined with mutations in Runx1 or Runx3 (131). CD4 derepression was also enhanced in DN thymocytes doubly deficient for Runx proteins and Mazr, supporting a cooperative role between these factors (131). Mazr likely regulates Thpok expression directly as it was found to bind the Thpok silencer element (130).…”

Section: Cis Elements and Epigenetic Regulation Of The Cd8 Locusmentioning

confidence: 99%

Heritable Gene Regulation in the CD4:CD8 T Cell Lineage Choice

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Littman

2017

Front. Immunol.

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The adaptive immune system is dependent on functionally distinct lineages of T cell antigen receptor αβ-expressing T cells that differentiate from a common progenitor in the thymus. CD4 + CD8+ progenitor thymocytes undergo selection following interaction with MHC class I and class II molecules bearing peptide self-antigens, giving rise to CD8 + cytotoxic and CD4 + helper or regulatory T cell lineages, respectively. The strict correspondence of CD4 and CD8 expression with distinct cellular phenotypes has made their genes useful surrogates for investigating molecular mechanisms of lineage commitment. Studies of Cd4 and Cd8 transcriptional regulation have uncovered cis-regulatory elements that are critical for mediating epigenetic modifications at distinct stages of development to establish heritable transcriptional programs. In this review, we examine the epigenetic mechanisms involved in Cd4 and Cd8 gene regulation during T cell lineage specification and highlight the features that make this an attractive system for uncovering molecular mechanisms of heritability.

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

Cited by 26 publications

References 33 publications

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

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

Priming of lineage-specifying genes by Bcl11b is required for lineage choice in post-selection thymocytes

Heritable Gene Regulation in the CD4:CD8 T Cell Lineage Choice

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