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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 (TR) with a dedicated suppressor function, controls TR lineage development. In humans and mice, Foxp3 deficiency results in a paucity of TR cells and a fatal breach in immunological tolerance, causing highly aggressive multi-organ autoimmune pathology1,2,3. Here, through genome-wide analysis combining chromatin immunoprecipitation with mouse genome tiling array profiling, we identify Foxp3 binding regions for 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 TR 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 TR lineage during differentiation and its proliferative and functional competence in the periphery.

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Figure 1: Analysis of Foxp3-bound genes using a mouse genome tiling array.
Figure 2: Distribution of Foxp3-binding regions within the mouse genome.
Figure 3: Foxp3 binding results in both activation and repression of its target genes.
Figure 4: Differential expression of prevalent functional groups of Foxp3-bound target genes in thymic and peripheral T R cells.
Figure 5: Foxp3 regulates miR-155 expression in T R cells.

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Acknowledgements

We thank K. Forbush and L. Karpik for assistance, and the members of our laboratory for discussions. This work was supported by the Cancer Research Institute (Y.Z.) and grants from the National Institutes of Health (A.Y.R.).

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Correspondence to Alexander Y. Rudensky.

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Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

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Zheng, Y., Josefowicz, S., Kas, A. et al. Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature 445, 936–940 (2007). https://doi.org/10.1038/nature05563

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