Acquisition of a Functional T Cell Receptor during T Lymphocyte Development Is Enforced by HEB and E2A Transcription Factors

Jones, Mark T.; Zhuang, Yuan

doi:10.1016/j.immuni.2007.10.014

Cited by 108 publications

(149 citation statements)

References 38 publications

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“…However, our data are consistent with the low abundance of E2A and presumably also of HEB in CD4 cells (32)(33)(34)(35) and with the fact that Mi-2b deletion impairs CD4 expression in DP, but not CD4, cells (11). Furthermore, combined HEB/E2A deletion does not impair CD4 expression in the peripheral CD4 cells, whereas the expression in DP cells is apparently affected (36). Together these data suggest that CD4 expression in CD4 cells requires some unknown factors.…”

Section: Figsupporting

confidence: 88%

Nucleoprotein structure of the CD4 locus: Implications for the mechanisms underlying CD4 regulation during T cell development

Wan

Zhang

et al. 2008

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

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A multiplex PCR assay for semiquantitative measurement of the CD4 enhancer (E), silencer (S), promoter (P), and the GADPH gene (asterisk). The agarose gel is stained with SYBR green, which gives less background staining and a wider dynamic range than ethidium bromide.(B and C) ChIP assays showing histone modifications (B) and transcription factor binding (C) at the CD4 locus. Two million cell equivalents of chromatin were used for each immunoprecipitation, and 10% of precipitated DNA was analyzed by PCR. At least two independent sources of cells were used for chromatin preparation, and PCR was repeated at least three times for each precipitated DNA sample. Input, sonicated chromatin equivalent to 2,000 cells and, thus, representing 0.1% of the starting material; DN, double-negative thymocytes from Rag2 Ϫ/Ϫ mice. (D) Quantitative analysis of ChIP samples. DNA from two experiments was quantified and the values averaged. Fold enrichment was then determined as described in Materials and Methods. R;S, DN3 cells isolated from Rag2 Ϫ/Ϫ ; silencer Ϫ/Ϫ mice as described for Fig. 3.

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Section: Figsupporting

confidence: 88%

Nucleoprotein structure of the CD4 locus: Implications for the mechanisms underlying CD4 regulation during T cell development

Wan

Zhang

et al. 2008

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

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“…In vitro reporter assays suggested that, among these, the 5 9 E box of the CD4-3 element is essential for enhancer activity. This E box was bound by HEB/E2A complexes in vitro, and DP thymocytes lacking HEB or both HEB and E2A had reduced Cd4 expression (11,12). In contrast, two E boxes, which are located in CD4-1 and at the 3 9 end of CD4-3, are not required for enhancer activity in vitro, and their functions have not been identified (9,10).…”

Section: Resultsmentioning

confidence: 97%

Transcription factor AP4 modulates reversible and epigenetic silencing of the Cd4 gene

Egawa

Littman

2011

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

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CD4 coreceptor expression is negatively regulated through activity of the Cd4 silencer in CD4 -CD8 -double-negative (DN) thymocytes and CD8 + cytotoxic lineage T cells. Whereas Cd4 silencing is reversed during transition from DN to CD4 + CD8 + double-positive stages, it is maintained through heritable epigenetic processes following its establishment in mature CD8 + T cells. We previously demonstrated that the Runx family of transcription factors is required for Cd4 silencing both in DN thymocytes and CD8 + T cells. However, additional factors that cooperate with Runx proteins in the process of Cd4 silencing remain unknown. To identify collaborating factors, we used microarray and RNAi-based approaches and found the basic helix-loop-helix ZIP transcription factor AP4 to have an important role in Cd4 regulation. AP4 interacts with Runx1 in cells in which Cd4 is silenced, and is required for Cd4 silencing in immature DN thymocytes through binding to the proximal enhancer. Furthermore, although AP4-deficient CD8 + T cells appeared to normally down-regulate CD4 expression, AP4 deficiency significantly increased the frequency of CD4-expressing effector/memory CD8 + T cells in mice harboring point mutations in the Cd4 silencer. Our results suggest that AP4 contributes to Cd4 silencing both in DN and CD8 + T cells by enforcing checkpoints for appropriate timing of CD4 expression and its epigenetic silencing. T he helper versus cytotoxic T-cell lineage decision in the thymus has long been studied as a model system for binary fate decisions. These two subsets of T cells are selected from a common precursor pool of CD4 + CD8 + double-positive (DP) thymocytes through interaction between clonally restricted TCRαβ chains and self-peptides presented on MHC class I or class II molecules expressed by thymic epithelial cells. During differentiation to the cytotoxic lineage, CD4 coreceptor expression is selectively silenced at the transcriptional level (Cd4 silencing), whereas CD8 expression from the Cd8a/Cd8b loci is transiently down-regulated and then restored through activation of postselection stage-specific enhancers (1). The Cd4 silencer, a cis-acting sequence with multiple transcription factor binding sites in the first intron of the Cd4 gene, is required for down-regulation of CD4 during the transition from the DP to CD8 single-positive (SP) stages as well as for repression at the CD4 -CD8 -double-negative (DN) stage of thymocyte differentiation (2, 3). Runx family transcription factors are required for Cd4 silencing through binding to the silencer, whereas ThPOK, induced following MHC class II-restricted selection, binds to the silencer to maintain active Cd4 expression in CD4SP thymocytes (4, 5). Runx proteins, particularly CD8 lineage-specific Runx3, and ThPOK not only regulate coreceptor expression but are also critically important for the development of the cytotoxic and helper lineages, respectively (5-8).Genetic studies have shown that the Cd4 silencer is required for the establishment of Cd4 silencing, but not for ...

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“…Many bHLH genes expressed during development and involved in the induction of cellular differentiation may be absent from this bHLH gene set. An example is the role that Tcfe2a (bHLHb21) has in thymic cell differentiation (Jones and Zhuang, 2007), but was absent from the bHLH gene set, Table 1. Therefore, further developmental analysis using the entire bHLH family is needed in the future.…”

Section: Discussionmentioning

confidence: 99%

Phylogenetic and expression analysis of the basic helix-loop-helix transcription factor gene family: genomic approach to cellular differentiation

2008

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A phylogenetic analysis of seven different species (human, mouse, rat, worm, fly, yeast, and plant) utilizing all (541) basic helix-loop-helix (bHLH) genes identified, including expressed sequence tags (EST), was performed. A super-tree involving six clades and a structural categorization involving the entire coding sequence was established. A nomenclature was developed based on clade distribution to discuss the functional and ancestral relationships of all the genes. The position/location of specific genes on the phylogenetic tree in relation to known bHLH factors allows for predictions of the potential functions of uncharacterized bHLH factors, including EST's. A genomic analysis using microarrays for four different mouse cell types (i.e. Sertoli, Schwann, thymic, and muscle) was performed and considered all known bHLH family members on the microarray for comparison. Cell-specific groups of bHLH genes helped clarify those bHLH genes potentially involved in cell specific differentiation. This phylogenetic and genomic analysis of the bHLH gene family has revealed unique aspects of the evolution and functional relationships of the different genes in the bHLH gene family.

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Acquisition of a Functional T Cell Receptor during T Lymphocyte Development Is Enforced by HEB and E2A Transcription Factors

Cited by 108 publications

References 38 publications

Nucleoprotein structure of the CD4 locus: Implications for the mechanisms underlying CD4 regulation during T cell development

Nucleoprotein structure of the CD4 locus: Implications for the mechanisms underlying CD4 regulation during T cell development

Transcription factor AP4 modulates reversible and epigenetic silencing of the Cd4 gene

Phylogenetic and expression analysis of the basic helix-loop-helix transcription factor gene family: genomic approach to cellular differentiation

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