Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Gene expression profiles of CD4SP Foxp3GFP-CD25+ Treg precursors and Foxp3GFP-CD25- thymocytes

ABSTRACT: We investigated at which stage of maturation commitment to a stable Foxp3-expressing phenotype takes place. We assessed stability of Foxp3 expression in thymic Foxp3+ Treg subsets of different maturity, defined by CD24 expression. Next we compared gene expression profiles of Foxp3+ Treg subsets (+) of different maturity (24lo, 24int, 24hi) and could identify a set of genes that were specifically up or downregulated in Foxp3+ Tregs, but not in Foxp3- conventional T cells, in a maturation-dependent manner. Gene expression of Foxp3+ Treg subsets (+) of different maturity (24lo, 24int, 24hi) compared to their Foxp3- conventional Tcell subsets (-) counterpart.

ORGANISM(S): Mus musculus

SUBMITTER: Robert Geffers

PROVIDER: E-GEOD-42021 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Active demethylation of the Foxp3 locus leads to the generation of stable regulatory T cells within the thymus.

Toker Aras A Engelbert Dirk D Garg Garima G Polansky Julia K JK Floess Stefan S Miyao Takahisa T Baron Udo U Düber Sandra S Geffers Robert R Giehr Pascal P Schallenberg Sonja S Kretschmer Karsten K Olek Sven S Walter Jörn J Weiss Siegfried S Hori Shohei S Hamann Alf A Huehn Jochen J

Journal of immunology (Baltimore, Md. : 1950) 20130218 7

Stable expression of Foxp3 in regulatory T cells (Tregs) depends on DNA demethylation at the Treg-specific demethylated region (TSDR), a conserved, CpG-rich region within the Foxp3 locus. The TSDR is selectively demethylated in ex vivo Tregs purified from secondary lymphoid organs, but it is unclear at which stage of Treg development demethylation takes place. In this study, we show that commitment to a stable lineage occurred during early stages of murine thymic Treg development by engraving of ...[more]

PMID: 23420886

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Project description:Regulatory T cells (Treg) contribute to the crucial immunological processes of self-tolerance and immune homeostasis. However, the mechanisms underlying Treg function and cell fate decisions to differentiate between Treg and conventional T cells (Tconv) remain to be fully elucidated, especially at the histone modification level. Covalent modifications of histones establish and maintain chromatin structure, and regulate gene transcription events by facilitating access to cis-elements by trans-acting factors during mammalian development and cellular differentiation. We aimed to investigate the role of the methylation form of histone modification as related to Treg function and phenotype. High-resolution maps of the genome-wide distribution of monomethylated histone H3 lysine 4, H3K4me1, and the trimethylated form H3K4me3 were generated for human activated conventional CD4+CD25+FOXP3- T cells (aTconv) and CD4+CD25+FOXP3+ regulatory T cells (Treg) by sequencing using the Solexa 1G Genetic Analyzer. We found 2115 H3K4me3 regions corresponding to proximal promoter regions; the genes associated with these regions in Treg cells included the crucial transcription factor forkhead box P3 (FOXP3) and the chemokine receptor CCR7. We also identified 41024 Treg cell type-specific H3K4me1 regions. The majority of the H3K4me1 regions differing between the Treg and aTconv cells were located at promoter-distal sites, some of which were selected and consolidated to further examine enhancer activity in in vitro reporter gene assays. The findings from our study provide a comprehensive genome-wide dataset of lineage-specific H3K4me1 and H3K4me3 patterns in Treg and aTconv cells, which may control the differentiation decision, lineage commitment and cell type-specific gene regulation. This basic principle is likely not confined to the two closely-related T cell populations, but may apply generally to somatic cell lineages in adult organisms. Genome-wide distribution of monomethylated histone H3 lysine 4, H3K4me1, and the trimethylated form H3K4me3 in human activated conventional CD4+CD25+FOXP3- T cells (aTconv) and CD4+CD25+FOXP3+ regulatory T cells (Treg) (5 samples in total)

Project description:We have previously developed an approach that fractionates genomic DNA fragments depending on their CpG density (methyl-CpG-immunoprecipitation, MCIp), and adapted this approach to identify regions that are differentially methylated in the two closely related regulatory T-cells (Treg cells) and conventional T-cells (Tconv cells). Because Treg cells naturally occur at a relatively low frequency, we used a previously established protocol to expand Treg cells from a stable naÃ¯ve Treg population that is characterized by the co-expression of CD4, CD25 and CD45RA. We separated gDNA of both expanded T cell lineages (Tregexp and Tconvexp) into unmethylated (CpG) and methylated pools (mCpG) using MCIp and compared cell type-specific differences in DNA methylation by co-hybridization of the two umethylated or the two methylated DNA subpopulations of Treg and Tconv, respectively, to these locus-wide custom tiling arrays. As enriched DNA-fragments from a cell type in the methylated fraction should be depleted in the unmethylated fraction, the signal intensities in CpG pool and mCpG pool hybridizations should complement themselves (âMirror-Imageâ approach) and thereby allow the identification of differentially methylated regions (DMR). Because we expected to find lineage-specific methylation differences with greater probability in regions associated with differential transcriptional activity, we limited our analysis to gene loci that showed cell type-specific gene expression in Treg versus Tconv cells plus a handful of control regions that were equally expressed in both cell types. The microarray used in this study covered 12 megabases of the human genome and contained 69 regions (with a median size of 100.000 kb) and 128 proximal promoter regions and 181 genes, which included a number of well known and functionally relevant genes like CD40LG, IFNG, FOXP3, IL2RA and CTLA4. Keywords: MCIp-on-chip; comparative genomic hybridization With MCIp gDNA from Treg or Tconv cells was separated into hypo- and hypermethylated pools. On each array, wheather the two hypomethylated fractions- one from Treg, the other from Tconv cells- or the two hypermethylated fractions were cohybridized. Two biological replicates.

Dataset Information

Gene expression profiles of CD4SP Foxp3GFP-CD25+ Treg precursors and Foxp3GFP-CD25- thymocytes

Publications

Active demethylation of the Foxp3 locus leads to the generation of stable regulatory T cells within the thymus.

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