The Ligase PIAS1 Restricts Natural Regulatory T Cell Differentiation by Epigenetic Repression

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Science  22 Oct 2010:
Vol. 330, Issue 6003, pp. 521-525
DOI: 10.1126/science.1193787

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CD4+Foxp3+ regulatory T (Treg) cells are important for maintaining immune tolerance. Understanding the molecular mechanism that regulates Treg differentiation will facilitate the development of effective therapeutic strategies against autoimmune diseases. We report here that the SUMO E3 ligase PIAS1 restricts the differentiation of natural Treg cells by maintaining a repressive chromatin state of the Foxp3 promoter. PIAS1 acts by binding to the Foxp3 promoter to recruit DNA methyltransferases and heterochromatin protein 1 for epigenetic modifications. Pias1 deletion caused promoter demethylation, reduced histone H3 methylation at Lys9, and enhanced promoter accessibility. Consistently, Pias1−/− mice displayed an increased natural Treg cell population and were resistant to the development of experimental autoimmune encephalomyelitis. Our studies have identified an epigenetic mechanism that negatively regulates the differentiation of natural Treg cells.

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