Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate
Autor: | Alexander Y. Rudensky, Katherine A. Forbush, Ye Zheng, Steven Z. Josefowicz, Xiao P. Peng, Ashutosh Chaudhry |
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Rok vydání: | 2010 |
Předmět: |
Male
Regulatory T cell Cellular differentiation Response element Population chemical and pharmacologic phenomena Thymus Gland Regulatory Sequences Nucleic Acid Biology Cell fate determination Response Elements T-Lymphocytes Regulatory Article Mice immune system diseases hemic and lymphatic diseases medicine Animals Cell Lineage Lymphocyte Count education Transcription factor Conserved Sequence Genetics Regulation of gene expression education.field_of_study Multidisciplinary FOXP3 Cell Differentiation Forkhead Transcription Factors hemic and immune systems DNA Methylation Chromatin Assembly and Disassembly Proto-Oncogene Proteins c-rel Cell biology Mice Inbred C57BL medicine.anatomical_structure Gene Expression Regulation CpG Islands Female |
Zdroj: | Nature. 463:808-812 |
ISSN: | 1476-4687 0028-0836 |
Popis: | 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-beta-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-beta-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. |
Databáze: | OpenAIRE |
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