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T Cells FOXP3 Target Genes in Natural Regulatory Genome-Wide Identification of Human

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T Cells FOXP3 Target Genes in Natural Regulatory Genome-Wide Identification of Human Genome-Wide Identification of Human FOXP3 Target Genes in Natural Regulatory T Cells This information is current as Timothy J. Sadlon, Bridget G. Wilkinson, Stephen Pederson, of September 26, 2021. Cheryl Y. Brown, Suzanne Bresatz, Tessa Gargett, Elizabeth L. Melville, Kaimen Peng, Richard J. D'Andrea, Gary G. Glonek, Gregory J. Goodall, Heddy Zola, M. Frances Shannon and Simon C. Barry J Immunol published online 16 June 2010 Downloaded from http://www.jimmunol.org/content/early/2010/06/16/jimmun ol.1000082 Supplementary http://www.jimmunol.org/content/suppl/2010/06/16/jimmunol.100008 http://www.jimmunol.org/ Material 2.DC1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 26, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published June 16, 2010, doi:10.4049/jimmunol.1000082 The Journal of Immunology Genome-Wide Identification of Human FOXP3 Target Genes in Natural Regulatory T Cells Timothy J. Sadlon,* Bridget G. Wilkinson,* Stephen Pederson,* Cheryl Y. Brown,* Suzanne Bresatz,* Tessa Gargett,* Elizabeth L. Melville,† Kaimen Peng,‡ Richard J. D’Andrea,x,{ Gary G. Glonek,‖ Gregory J. Goodall,{ Heddy Zola,# M. Frances Shannon,‡ and Simon C. Barry*,† The transcription factor FOXP3 is essential for the formation and function of regulatory T cells (Tregs), and Tregs are essential for maintaining immune homeostasis and tolerance. This is demonstrated by a lethal autoimmune defect in mice lacking Foxp3 and in immunodysregulation polyendocrinopathy enteropathy X-linked syndrome patients. However, little is known about the molecular basis of human FOXP3 function or the relationship between direct and indirect targets of FOXP3 in human Tregs. To investigate Downloaded from this, we have performed a comprehensive genome-wide analysis for human FOXP3 target genes from cord blood Tregs using chromatin immunoprecipitation array profiling and expression profiling. We have identified 5579 human FOXP3 target genes and derived a core Treg gene signature conserved across species using mouse chromatin immunoprecipitation data sets. A total of 739 of the 5579 FOXP3 target genes were differentially regulated in Tregs compared with Th cells, thus allowing the identification of a number of pathways and biological functions overrepresented in Tregs. We have identified gene families including cell surface + molecules and microRNAs that are differentially expressed in FOXP3 Tregs. In particular, we have identified a novel role for http://www.jimmunol.org/ peptidase inhibitor 16, which is expressed on the cell surface of >80% of resting human CD25+FOXP3+ Tregs, suggesting that in conjunction with CD25 peptidase inhibitor 16 may be a surrogate surface marker for Tregs with potential clinical application. The Journal of Immunology, 2010, 185: 000–000. egulatory T cells (Tregs) are essential “master regulators” appears to require Treg function (8). The ability to monitor and of tolerance (1), allowing effective responses to infection manipulate Tregs may improve diagnosis or therapeutic interven- R and non-self Ags while preventing autoimmunity and tion for autoimmune diseases. To achieve this, sensitive and spe- immune pathology (2). Although there are several subsets of cells cific biomarkers are required, but currently, however, there are with regulatory capacity (reviewed in Ref. 3), it is clear that the limited markers available. This genome-wide study of human Tregs by guest on September 26, 2021 CD4+CD25+FOXP3+ natural Tregs (nTregs) is a key participant in takes an unbiased approach for identification of novel markers the orchestration of tolerance, because without these cells an early and gene regulation networks. onset aggressive autoimmune condition arises in both mouse and The forkhead (FKH) transcription factor FOXP3 is expressed man (4–6). Furthermore, a number of autoimmune diseases in- constitutively in natural CD4+ Tregs and has been shown to be volve a perturbation in Treg numbers or function (reviewed in essential for nTreg function (9). FOXP3 is a member of the P Ref. 7), and control of the local response to acute tissue damage subfamily of the FKH family of transcription factors sharing a number of common features including a C2H2 zinc finger, a leu- cine zipper, and a FKH DNA-binding domain (10). These domains # *Molecular Immunology Laboratory and Leukocyte Biology Laboratory, Women’s are involved in DNA binding, nuclear transport (11), homomeric and Children’s Health Research Institute, Women’s and Children’s Hospital, North Adelaide; †Discipline of Paediatrics and ‖Discipline of Statistics, School of Mathe- and heteromeric complex formation (12), and transcriptional re- x matical Sciences, University of Adelaide; Department of Haematology and Oncol- pressor activity (12, 13). Mechanisms of action of FOXP3 in Tregs ogy, Queen Elizabeth Hospital; {Centre for Cancer Biology, South Australia Pathology, Adelaide, South Australia; and ‡Gene Expression and Epigenomics have been identified in mouse, but less is known about its role Group, Genome Biology Program, Biomolecular Resource Facility, John Curtin in the development and function of human Tregs (reviewed in Ref. School for Medical Research, Australian National University, Canberra, Australian 12). In particular, the existence of two major human-specific Capital Territory, Australia FOXP3 isoforms (14) with different regulatory capacities (15, Received for publication January 12, 2010. Accepted for publication May 3, 2010. 16) and the transient induction of FOXP3 following activation of The microarray data presented in this article have been submitted to Gene Expression CD4+CD252 non-Tregs in humans (17) suggest a degree of spe- Omnibus under accession numbers GSE20995 and GSE20934. cies-specific function by, and regulation of, FOXP3. Address correspondence and reprint requests to Dr. Simon C. Barry, Molecular Immunology Laboratory, Discipline of Paediatrics, University of Adelaide, and In mouse and human Tregs, FOXP3 not only represses but also Women’s and Children’s Health Research Institute, Women’s and Children’s Hospi- can induce gene expression, although the mechanism by which tal, North Adelaide, South Australia 5006, Australia. E-mail address: simon.barry@ FOXP3 can negatively regulate transcription of some genes, such adelaide.edu.au as IL2, but positively regulate others, such as CD25 and CTLA4,is The online version of this article contains supplemental material. still unclear (reviewed in Ref. 10). FOXP3 interacts with multiple Abbreviations used in this paper: ChIP-on-chip, chromatin immunoprecipitation array profiling; DE, differentially expressed; FDR, false discovery rate; FKH, forkhead; transcription factors known to be involved in activation, differ- + miR, microRNA; mRNA, messenger RNA; nTreg, natural regulatory T cell; PI16, entiation, and response of CD4 T cells to TCR stimulation, in- peptidase inhibitor 16; qPCR, quantitative real-time PCR; ROR, retinoic acid recep- cluding NFAT, NF-kB, Runx1, retinoic acid receptor-related tor-related orphan receptor; Treg, regulatory T cell; TSS, transcription start site. orphan receptors (RORs) (RORa and RORgT), IFN regulatory Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 factor 4, STAT3, and Jun (15, 16, 18–24). FOXP3 may act as www.jimmunol.org/cgi/doi/10.4049/jimmunol.1000082 2 FOXP3 TARGET GENES IN HUMAN nTregs a transcriptional corepressor, because FKH domain-independent hybridization to Affymetrix Human Tiling 2.0R arrays was by whole- inhibition of the trans-activation activity of NF-kB, CREB, and genome amplification (Sigma-Aldrich GenomePlex Whole Genome Am- RORa has been reported (16, 21). FOXP3 is also likely to mod- plification Kit) (31) adapted for Affymetrix labeling systems by the inclu- sion of 0.11 mM dUTP in the amplification reaction. Amplified material ulate gene expression through epigenetic mechanisms, such as was purified using a PCR clean-up kit (Qiagen, Valencia, CA). Data from chromatin remodeling and histone deacetylation (25, 26). It is two independent ChIP-on-chip experiments were analyzed as replicates evident that the composition and activity of the FOXP3 regulatory using Model-based Analysis of Tiling-array (32). Labeling and complex is dynamic and is influenced by external stimuli acting hybridization of amplified material to Affymetrix human tiling arrays was carried out at the Biomolecular Resource Facility (John Curtin School of partly through the posttranslational modification of FOXP3 (27, Medical Research, Australian National University). Data files for this 28). These observations demonstrate the complex nature of the experiment are lodged on Gene Expression Omnibus (accession no. interaction of FOXP3 with its target genes. GSE20995; www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE20995). In this article, we identify molecular targets of human FOXP3 in
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