title: The enhancer and promoter landscape of human regulatory and conventional T-cell subpopulations.
abstract: CD4(+)CD25(+)FOXP3(+) human regulatory T cells (Tregs) are essential for self-tolerance and immune homeostasis. Here, we describe the promoterome of CD4(+)CD25(high)CD45RA(+) naïve and CD4(+)CD25(high)CD45RA(-) memory Tregs and their CD25(-) conventional T-cell (Tconv) counterparts both before and after in vitro expansion by cap analysis of gene expression (CAGE) adapted to single-molecule sequencing (HeliScopeCAGE). We performed comprehensive comparative digital gene expression analyses and revealed novel transcription start sites, of which several were validated as alternative promoters of known genes. For all in vitro expanded subsets, we additionally generated global maps of poised and active enhancer elements marked by histone H3 lysine 4 monomethylation and histone H3 lysine 27 acetylation, describe their cell type-specific motif signatures, and evaluate the role of candidate transcription factors STAT5, FOXP3, RUNX1, and ETS1 in both Treg- and Tconv-specific enhancer architectures. Network analyses of gene expression data revealed additional candidate transcription factors contributing to cell type specificity and a transcription factor network in Tregs that is dominated by FOXP3 interaction partners and targets. In summary, we provide a comprehensive and easily accessible resource of gene expression and gene regulation in human Treg and Tconv subpopulations.
authors.affiliation: Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany;
authors.forename: Christian
authors.initials: C
authors.lastname: Schmidl
authors.forename: Leo
authors.initials: L
authors.lastname: Hansmann
authors.forename: Timo
authors.initials: T
authors.lastname: Lassmann
authors.forename: Piotr J
authors.initials: PJ
authors.lastname: Balwierz
authors.forename: Hideya
authors.initials: H
authors.lastname: Kawaji
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Itoh
authors.forename: Jun
authors.initials: J
authors.lastname: Kawai
authors.forename: Sayaka
authors.initials: S
authors.lastname: Nagao-Sato
authors.forename: Harukazu
authors.initials: H
authors.lastname: Suzuki
authors.forename: Reinhard
authors.initials: R
authors.lastname: Andreesen
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Hayashizaki
authors.forename: Alistair R R
authors.initials: AR
authors.lastname: Forrest
authors.forename: Piero
authors.initials: P
authors.lastname: Carninci
authors.forename: Petra
authors.initials: P
authors.lastname: Hoffmann
authors.forename: Matthias
authors.initials: M
authors.lastname: Edinger
authors.forename: Michael
authors.initials: M
authors.lastname: Rehli
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D016208:Databases, Factual; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D051858:Forkhead Transcription Factors / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006657:Histones / Q000378:metabolism; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D019169:Jurkat Cells; D008239:Lysine / Q000378:metabolism; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012313:RNA / Q000378:metabolism; D017422:Sequence Analysis, DNA; D016176:T-Lymphocyte Subsets / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D006657:Histones; D053645:Interleukin-2 Receptor alpha Subunit; D014157:Transcription Factors; D012313:RNA; D008239:Lysine