e n i c i d e M l a t n e m i r e p x E f o l a n r u o J e h T CORRESPONDENCE Toshinori Nakayama: tnakayama@faculty.chiba-u.jp Abbreviations used: CBP, CREB-binding protein; ChIP, chromatin immunoprecipita- tion; EMSA, electrophoretic mobility shift assay; LCR, locus control region; MLL, mixed- lineage leukemia; mRNA, mes- senger RNA; PcG, polycomb group; PRE, polycomb re- sponse element; RNAPII, RNA polymerase II; TRE, trithorax response element; TrxG, tritho- rax group; TSA, trichostatin A. The Rockefeller University Press $30.00 J. Exp. Med. Vol. 207 No. 11 2493-2506 www.jem.org/cgi/doi/10.1084/jem.20100760 A r t i c l e STAT6-mediated displacement of polycomb by tr ithorax complex establishes long-ter m maintenance of GATA3 expression in T helper type 2 cells Atsushi Onodera,1 Masakatsu Yamashita,1 Yusuke Endo,1 Makoto Kuwahara,1 Soichi Tofukuji,1 Hiroyuki Hosokawa,1 Akinori Kanai,2 Yutaka Suzuki,2 and Toshinori Nakayama1 1Department of Immunology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan 2Laboratory of Functional Genomics, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa-Shi, Chiba 277-8562, Japan Polycomb group (PcG) and trithorax group (TrxG) complexes exert opposing effects on the maintenance of the transcriptional status of the developmentally regulated Hox genes. In this study, we show that activation of STAT6 induces displacement of the PcG complex by the TrxG complex at the upstream region of the gene encoding GATA3, a transcription factor essential for T helper type 2 (Th2) cell differentiation. Once Th2 cells differentiate, TrxG complex associated with the TrxG component Menin binds to the whole GATA3 gene locus, and this binding is required for the long-term maintenance of expression of GATA3 and Th2 cytokine. Thus, STAT6-mediated displacement of PcG by the TrxG complex establishes subsequent STAT6-independent maintenance of GATA3 expression in Th2 cells via the recruitment of the Menin–TrxG complex. Immunity against different classes of microor- ganisms is directed by specialized effector CD4 Th subsets, of which the best characterized are Th1, Th2, and Th17 cells (Mosmann and Coffman, 1989; Reiner and Locksley, 1995; Korn et al., 2009). IL-12–induced activation of STAT4 is required for Th1 cell differentiation, whereas IL-4–induced STAT6 activation is crucial for Th2 cell differentiation. Master transcription factors that regulate Th1/Th2/ Th17 cell differentiation have been identified. T cell–specific T-box transcription factor (T-bet) appears to be a key factor for Th1 cell differen- tiation (Szabo et al., 2002), GATA3 for Th2 (Zheng and Flavell, 1997; Lee et al., 2000; Zhu et al., 2010), and ROR-t (retinoid-related orphan receptor t) and ROR- for Th17 (Ivanov et al., 2006; Yang et al., 2008). GATA3 is predominantly expressed in T lymphocytes and the embryonic brain (Yamamoto et al., 1990). In peripheral CD4 T cells, the activation of STAT6 induces high- level expression of GATA3 messenger RNA (mRNA), although the precise mechanisms underlying the STAT6-induced GATA3 tran- scription remain unclear. Changes in histone modification such as H3-K9/14 acetylation and the H3-K4 methylation at the Th2 cyto- kine gene loci occur during Th2 cell differen- tiation (Löhning et al., 2002; Ansel et al., 2006; Nakayama and Yamashita, 2008), and this is mediated primarily by GATA3 in peripheral CD4 and CD8 T cells. High-level expression of GATA3 is required for producing large amounts of Th2 cytokines in established Th2 cells (Pai et al., 2004; Yamashita et al., 2004; Zhu et al., 2004). The polycomb group (PcG) complex an- tagonizes the effect of the trithorax group (TrxG) complex (Ringrose and Paro, 2004). The TrxG complex establishes a chromatin structure permissive for transcription, in part, through the induction of methylation at histone © 2010 Onodera et al. This article is distributed under the terms of an Attri- bution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncom- mercial–Share Alike 3.0 Unported license, as described at http://creativecommons .org/licenses/by-nc-sa/3.0/). 2493