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Science 330 (6003): 521-525

Copyright © 2010 by the American Association for the Advancement of Science

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

Bin Liu,1,*,{dagger} Samuel Tahk,1,* Kathleen M. Yee,2 Guoping Fan,3 Ke Shuai1,2,{dagger}

Abstract: 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.

1 Division of Hematology-Oncology, Department of Medicine, 11-934 Factor Building, 10833 Le Conte Avenue, University of California, Los Angeles, Los Angeles, CA 90095, USA.
2 Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
3 Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.

* These authors contributed equally to this manuscript.

{dagger} To whom correspondence should be addressed. E-mail: bliu{at}ucla.edu (B.L.); kshuai{at}mednet.ucla.edu (K.S.)

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