title: Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells.
abstract: Transcription factor Foxp3 (forkhead box P3), restricted in its expression to a specialized regulatory CD4+ T-cell subset (T(R)) with a dedicated suppressor function, controls T(R) lineage development. In humans and mice, Foxp3 deficiency results in a paucity of T(R) cells and a fatal breach in immunological tolerance, causing highly aggressive multi-organ autoimmune pathology. Here, through genome-wide analysis combining chromatin immunoprecipitation with mouse genome tiling array profiling, we identify Foxp3 binding regions for approximately 700 genes and for an intergenically encoded microRNA. We find that a large number of Foxp3-bound genes are up- or downregulated in Foxp3+ T cells, suggesting that Foxp3 acts as both a transcriptional activator and repressor. Foxp3-mediated regulation unique to the thymus affects, among others, genes encoding nuclear factors that control gene expression and chromatin remodelling. In contrast, Foxp3 target genes shared by the thymic and peripheral T(R) cells encode primarily plasma membrane proteins, as well as cell signalling proteins. Together, our studies suggest that distinct transcriptional sub-programmes implemented by Foxp3 establish T(R) lineage during differentiation and its proliferative and functional competence in the periphery.
authors.affiliation: Department of Immunology, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Ye
authors.initials: Y
authors.lastname: Zheng
authors.forename: Steven Z
authors.initials: SZ
authors.lastname: Josefowicz
authors.forename: Arnold
authors.initials: A
authors.lastname: Kas
authors.forename: Tin-Tin
authors.initials: TT
authors.lastname: Chu
authors.forename: Marc A
authors.initials: MA
authors.lastname: Gavin
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Rudensky
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics*; D016678:Genome / Q000235:genetics; D023281:Genomics; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse