Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate Journal Article
| Authors: | Zheng, Y.; Josefowicz, S.; Chaudhry, A.; Peng, X. P.; Forbush, K.; Rudensky, A. Y. |
| Article Title: | Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate |
| Abstract: | Immune homeostasis is dependent on tight control over the size of a population of regulatory T (T reg) cells capable of suppressing over-exuberant immune responses. The T reg cell subset is comprised of cells that commit to the T reg lineage by upregulating the transcription factor Foxp3 either in the thymus (tT reg) or in the periphery (iT reg). Considering a central role for Foxp3 in T reg cell differentiation and function, we proposed that conserved non-coding DNA sequence (CNS) elements at the Foxp3 locus encode information defining the size, composition and stability of the T reg cell population. Here we describe the function of three Foxp3 CNS elements (CNS1-3) in T reg cell fate determination in mice. The pioneer element CNS3, which acts to potently increase the frequency of T reg cells generated in the thymus and the periphery, binds c-Rel in in vitro assays. In contrast, CNS1, which contains a TGF-Β-NFAT response element, is superfluous for tT reg cell differentiation, but has a prominent role in iT reg cell generation in gut-associated lymphoid tissues. CNS2, although dispensable for Foxp3 induction, is required for Foxp3 expression in the progeny of dividing T reg cells. Foxp3 binds to CNS2 in a Cbf-Β-Runx1 and CpG DNA demethylation-dependent manner, suggesting that Foxp3 recruitment to this cellular memory module facilitates the heritable maintenance of the active state of the Foxp3 locus and, therefore, T reg lineage stability. Together, our studies demonstrate that the composition, size and maintenance of the T reg cell population are controlled by Foxp3 CNS elements engaged in response to distinct cell-extrinsic or-intrinsic cues. © 2010 Macmillan Publishers Limited. All rights reserved. |
| Keywords: | controlled study; nonhuman; transcription factor foxp3; forkhead transcription factors; animal cell; mouse; cytology; animals; mice; mus; cell division; gene expression; transforming growth factor beta; protein binding; gene locus; cell fate; cell differentiation; dna methylation; mice, inbred c57bl; cell lineage; gene expression regulation; lymphocyte differentiation; regulatory t lymphocyte; dna; immune response; conserved sequence; thymus; t-lymphocytes, regulatory; thymus gland; chromatin; cpg island; cpg islands; response elements; hominid; homeostasis; dna responsive element; transcription factor nfat; lymphocyte count; heritability; chromatin assembly and disassembly; transcription factor runx1; regulatory sequences, nucleic acid; demethylation; transcription factor rel; intestine lymphatic tissue; proto-oncogene proteins c-rel |
| Journal Title: | Nature |
| Volume: | 463 |
| Issue: | 7282 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2010-02-11 |
| Start Page: | 808 |
| End Page: | 812 |
| Language: | English |
| DOI: | 10.1038/nature08750 |
| PUBMED: | 20072126 |
| PROVIDER: | scopus |
| PMCID: | PMC2884187 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 49" - "Export Date: 20 April 2011" - "CODEN: NATUA" - "Source: Scopus" |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work