We are analyzing https://link.springer.com/article/10.1007/s00109-010-0642-1.

Title:
Methylation matters: binding of Ets-1 to the demethylated Foxp3 gene contributes to the stabilization of Foxp3 expression in regulatory T cells | Journal of Molecular Medicine
Description:
The forkhead-box protein P3 (Foxp3) is a key transcription factor for the development and suppressive activity of regulatory T cells (Tregs), a T cell subset critically involved in the maintenance of self-tolerance and prevention of over-shooting immune responses. However, the transcriptional regulation of Foxp3 expression remains incompletely understood. We have previously shown that epigenetic modifications in the CpG-rich Treg-specific demethylated region (TSDR) in the Foxp3 locus are associated with stable Foxp3 expression. We now demonstrate that the methylation state of the CpG motifs within the TSDR controls its transcriptional activity rather than a Treg-specific transcription factor network. By systematically mutating every CpG motif within the TSDR, we could identify four CpG motifs, which are critically determining the transcriptional activity of the TSDR and which serve as binding sites for essential transcription factors, such as CREB/ATF and NF-κB, which have previously been shown to bind to this element. The transcription factor Ets-1 was here identified as an additional molecular player that specifically binds to the TSDR in a demethylation-dependent manner in vitro. Disruption of the Ets-1 binding sites within the TSDR drastically reduced its transcriptional enhancer activity. In addition, we found Ets-1 bound to the demethylated TSDR in ex vivo isolated Tregs, but not to the methylated TSDR in conventional CD4+ T cells. We therefore propose that Ets-1 is part of a larger protein complex, which binds to the TSDR only in its demethylated state, thereby restricting stable Foxp3 expression to the Treg lineage.
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Keywords {🔍}

foxp, tsdr, cells, expression, binding, transcription, activity, article, pubmed, google, scholar, ets, transcriptional, cas, luciferase, regulatory, factor, tregs, fig, enhancer, cpg, cell, methylation, dna, demethylated, conventional, reporter, promoter, sites, protein, immunol, performed, regulation, factors, murine, gene, motifs, vitro, assays, control, function, shown, methylated, values, data, molecular, stable, crebatf, nfκb, human,

Topics {✒️}

methyl-group donor s-adenosylmethionine early b-cell-specific mb-1 nf-κb-subunit c-rel binds tgf-β-inducible early gene-1 natural tregs = foxp3+cd25+cd4+cd8− nf-κb-subunit c-rel tgf-β-induced foxp3 expression pcpgl-cmv/ef1 vector [35] tgf-β-induced foxp3+ tregs specific pathogen-free conditions tsdr-foxpro-luc reporter vector pgl3-luciferase-reporter vector runt-related transcription factor-1 treg-specific demethylated region transforming growth factor-β cells = foxp3−cd25−cd4+cd8− fusion-fx7 imaging-system runx1-cbfbeta transcription complex forkhead-box protein p3 graft-versus-host disease [2] inter-species conservation plots highest inter-species conservation anti-cd4-fluorescein isothiocyanate cell-restricted dna methyltransferase-1 wilcoxon signed-rank test tgf-β-sensitive enhancer multi-component protein complex tgf-β-induced tregs site-specific mutagenesis resulting multi-step selection procedure transcription factors creb/atf foxp3-dependent developmental program single-stranded dna-oligonucleotides article download pdf 1 μg/ml anti-cd3 transcription factor repertoire anti-cd25-apc antibody nf-κb-binding site nf-κb binding site nf-κb binding sites distinct demethylation-dependent interactions 250 mm tris-hcl ph 8 cd4+cd25+foxp3gfp+ tregs full size image anti-fitc-multisort microbeads stat6-deficient inducible tgf-β-mediated signals human cd4+cd25+ regulatory 1 μg/ml anti-cd28 demethylating drug 5-aza-2′-deoxycytidine

Questions {❓}

A central question still remains to be solved: Which signals and pathways lead to the demethylation of the TSDR during differentiation into stable Tregs?
Huehn J, Polansky JK, Hamann A (2009) Epigenetic control of FOXP3 expression: the key to a stable regulatory T-cell lineage?

Schema {🗺️}

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         headline:Methylation matters: binding of Ets-1 to the demethylated Foxp3 gene contributes to the stabilization of Foxp3 expression in regulatory T cells
         description:The forkhead-box protein P3 (Foxp3) is a key transcription factor for the development and suppressive activity of regulatory T cells (Tregs), a T cell subset critically involved in the maintenance of self-tolerance and prevention of over-shooting immune responses. However, the transcriptional regulation of Foxp3 expression remains incompletely understood. We have previously shown that epigenetic modifications in the CpG-rich Treg-specific demethylated region (TSDR) in the Foxp3 locus are associated with stable Foxp3 expression. We now demonstrate that the methylation state of the CpG motifs within the TSDR controls its transcriptional activity rather than a Treg-specific transcription factor network. By systematically mutating every CpG motif within the TSDR, we could identify four CpG motifs, which are critically determining the transcriptional activity of the TSDR and which serve as binding sites for essential transcription factors, such as CREB/ATF and NF-κB, which have previously been shown to bind to this element. The transcription factor Ets-1 was here identified as an additional molecular player that specifically binds to the TSDR in a demethylation-dependent manner in vitro. Disruption of the Ets-1 binding sites within the TSDR drastically reduced its transcriptional enhancer activity. In addition, we found Ets-1 bound to the demethylated TSDR in ex vivo isolated Tregs, but not to the methylated TSDR in conventional CD4+ T cells. We therefore propose that Ets-1 is part of a larger protein complex, which binds to the TSDR only in its demethylated state, thereby restricting stable Foxp3 expression to the Treg lineage.
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            Gene expression
            Transcription factors
            Molecular Medicine
            Human Genetics
            Internal Medicine
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      description:The forkhead-box protein P3 (Foxp3) is a key transcription factor for the development and suppressive activity of regulatory T cells (Tregs), a T cell subset critically involved in the maintenance of self-tolerance and prevention of over-shooting immune responses. However, the transcriptional regulation of Foxp3 expression remains incompletely understood. We have previously shown that epigenetic modifications in the CpG-rich Treg-specific demethylated region (TSDR) in the Foxp3 locus are associated with stable Foxp3 expression. We now demonstrate that the methylation state of the CpG motifs within the TSDR controls its transcriptional activity rather than a Treg-specific transcription factor network. By systematically mutating every CpG motif within the TSDR, we could identify four CpG motifs, which are critically determining the transcriptional activity of the TSDR and which serve as binding sites for essential transcription factors, such as CREB/ATF and NF-κB, which have previously been shown to bind to this element. The transcription factor Ets-1 was here identified as an additional molecular player that specifically binds to the TSDR in a demethylation-dependent manner in vitro. Disruption of the Ets-1 binding sites within the TSDR drastically reduced its transcriptional enhancer activity. In addition, we found Ets-1 bound to the demethylated TSDR in ex vivo isolated Tregs, but not to the methylated TSDR in conventional CD4+ T cells. We therefore propose that Ets-1 is part of a larger protein complex, which binds to the TSDR only in its demethylated state, thereby restricting stable Foxp3 expression to the Treg lineage.
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         DNA methylation
         Gene expression
         Transcription factors
         Molecular Medicine
         Human Genetics
         Internal Medicine
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      name:Immunobiology, Leibniz-Center for Medicine and Biosciences, Borstel, Germany
      name:Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
      name:Experimental Rheumatology, Charité University Medicine Berlin and German Rheumatism Research Center, Berlin, Germany
      name:Experimental Rheumatology, Charité University Medicine Berlin and German Rheumatism Research Center, Berlin, Germany
      name:Signal Transduction, German Rheumatism Research Center, Berlin, Germany
      name:Signal Transduction, German Rheumatism Research Center, Berlin, Germany
      name:Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
      name:Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
      name:Experimental Rheumatology, Charité University Medicine Berlin and German Rheumatism Research Center, Berlin, Germany
      name:Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany

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