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

Yu, Ming; Wan, Mimi; Zhang, Jianmin; Wu, Jie; Khatri, Rohini; Tian, Chao

doi:10.1073/pnas.0800810105

Cited by 33 publications

(43 citation statements)

References 39 publications

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“…Upon β selection, silencer function is potentially attenuated in part by Runx1 down-regulation, whereas the Cd4 gene remains inactive in an AP4-dependent manner until developing thymocytes go through the DN4 stage. Premature CD4 expression in DN thymocytes triggers bypassing of the β-selection checkpoint, resulting in generation of double-positive thymocytes even without successful Tcrb rearrangements (15,16). A similar phenotype was observed in our analysis using AP4/Rag2 compound mutant mice.…”

Section: Discussionsupporting

confidence: 85%

“…2D). Similar phenotypes have been reported in mice ectopically expressing transgenic CD4 in DN3 thymocytes, lacking the Cd4 silencer, or lacking the E2A E-box protein (15)(16)(17). In control mice, CD4 remained silenced in intracellular TCRβ (icTCRβ)-expressing thymocytes that down-regulated CD25 following β selection, and only a small fraction of cells started to express CD4 at the DN4 stage (Fig.…”

Section: Ap4 Is Required For Cd4supporting

confidence: 80%

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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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Section: Discussionsupporting

confidence: 85%

Section: Ap4 Is Required For Cd4supporting

confidence: 80%

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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“…The HEB and E2A bHLH transcription factors, which are crucial for E4 P -mediated Cd4 activation between the DN and DP stages (Jones and Zhuang, 2007;Sawada and Littman, 1993), are preloaded onto E4 P at the DN stage (Yu et al, 2008). In the presence of S4, however, p300 recruitment to E4 P , and thus transcriptional activation, is impaired (Yu et al, 2008). This antagonism of p300 recruitment could be mediated by longrange interactions between S4, bound by Runx1, and E4 P , as was recently reported (Jiang and Peterlin, 2008).…”

Section: Epigenetic Regulation Of the Cd4 Locussupporting

confidence: 53%

“…One model that can be constructed from recent data would involve active antagonism of E4 P function by Runx1. The HEB and E2A bHLH transcription factors, which are crucial for E4 P -mediated Cd4 activation between the DN and DP stages (Jones and Zhuang, 2007;Sawada and Littman, 1993), are preloaded onto E4 P at the DN stage (Yu et al, 2008). In the presence of S4, however, p300 recruitment to E4 P , and thus transcriptional activation, is impaired (Yu et al, 2008).…”

Section: Epigenetic Regulation Of the Cd4 Locusmentioning

confidence: 99%

The Epigenetic Landscape of Lineage Choice: Lessons From the Heritability of Cd4 and Cd8 Expression

Gialitakis¹,

Sellars²,

Littman³

2011

Current Topics in Microbiology and Immunology

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Developing αβ T cells choose between the helper and cytotoxic lineages, depending upon the specificity of their T cell receptors for MHC molecules. The expression of the CD4 co-receptor on helper cells and the CD8 co-receptor on cytotoxic cells is intimately linked to this decision, and their regulation at the transcriptional level has been the subject of intense study to better understand lineage choice. Indeed, as the fate of developing T cells is decided, the expression status of these genes is accordingly locked. Genetic models have revealed important transcriptional elements and the ability to manipulate these elements in the framework of development has added a new perspective on the temporal nature of their function and the epigenetic maintenance of gene expression. We examine here the novel insights into epigenetic mechanisms that have arisen through the study of these genes.

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“…ChIP was performed as described (Yu et al, 2008;Lai et al, 2009) except that Dynal protein G magnetic beads (Invitrogen) instead of Sepharose beads were used to capture chromatin, which produced negligible nonspecific signals, and the DNA was quantified by real-time, multiplex PCR. The abundance of targets in the ChIP DNA, normalized to that in the input, was plotted relative to the abundance of similarly normalized control regions as fold enrichment over the control.…”

Section: Chromatin Immunoprecipitation (Chip)mentioning

confidence: 99%

Inducible mouse models illuminate parameters influencing epigenetic inheritance

Wan

Wang

et al. 2013

Development

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SUMMARYEnvironmental factors can stably perturb the epigenome of exposed individuals and even that of their offspring, but the pleiotropic effects of these factors have posed a challenge for understanding the determinants of mitotic or transgenerational inheritance of the epigenetic perturbation. To tackle this problem, we manipulated the epigenetic states of various target genes using a tetracycline-dependent transcription factor. Remarkably, transient manipulation at appropriate times during embryogenesis led to aberrant epigenetic modifications in the ensuing adults regardless of the modification patterns, target gene sequences or locations, and despite lineage-specific epigenetic programming that could reverse the epigenetic perturbation, thus revealing extraordinary malleability of the fetal epigenome, which has implications for 'metastable epialleles'. However, strong transgenerational inheritance of these perturbations was observed only at transgenes integrated at the Col1a1 locus, where both activating and repressive chromatin modifications were heritable for multiple generations; such a locus is unprecedented. Thus, in our inducible animal models, mitotic inheritance of epigenetic perturbation seems critically dependent on the timing of the perturbation, whereas transgenerational inheritance additionally depends on the location of the perturbation. In contrast, other parameters examined, particularly the chromatin modification pattern and DNA sequence, appear irrelevant.

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

Cited by 33 publications

References 39 publications

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

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

The Epigenetic Landscape of Lineage Choice: Lessons From the Heritability of Cd4 and Cd8 Expression

Inducible mouse models illuminate parameters influencing epigenetic inheritance

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