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.
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Genes affected by positive or negative regulators significantly overlap with genes bound by key CD4+ transcription factors Foxp3, Batf, Irf4, and ROR-γt.
“The genes affected by either positive or negative regulators also significantly overlap with those bound by key CD4+ transcription factors (e.g., Foxp326,27, Batf, Irf4, and ROR-γt28,29, Xiao et al., unpublished data).”
From Dynamic regulatory network controlling TH17 cell differentiation (2013) · cites this paper as [27]
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- Authors
- Zheng, Y., Josefowicz, S. Z., Kas, A., Chu, T.-T., Gavin, M. A., & Rudensky, A. Y.
- Affiliations
- University of Washington (US)
- Amgen (United States) (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Rudensky, Alexander Y.
- Venue
- Nature
- Published
- 2007-01-21
- Volume
- 445
- Issue
- 7130
- Pages
- 936-940
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1992641327
- Cited by
- 835
- References
- 19
- Citations by year
- 2026: 11 · 2025: 12 · 2024: 22 · 2023: 17 · 2022: 26 · 2021: 30 · 2020: 36 · 2019: 48 · 2018: 36 · 2017: 37 · 2016: 32 · 2015: 40 · 2014: 49 · 2013: 62 · 2012: 63
- FWCI
- 31.71
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Cancer Research Institute
- National Institutes of Health
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- Foxp3, regulatory T cells, transcriptional regulation, chromatin binding, microRNA, thymic Treg development, chromatin remodeling, nuclear transcription factors, immune tolerance, autoimmune disease, CD4+ T cells
- MeSH terms
- Animals, Cell Differentiation, Gene Expression Regulation, Mice, Inbred C57BL, Protein Binding, Thymus Gland, Genome, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Genomics, T-Lymphocytes, Regulatory, Mice, Forkhead Transcription Factors
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