Differential roles of epigenetic changes and Foxp3 expression in regulatory T cell-specific transcriptional regulation

Morikawa, H.; Ohkura, N.; Vandenbon, A.; Itoh, M.; Nagao-Sato, S.; Kawaji, H.; Lassmann, T.; Carninci, P.; Hayashizaki, Y.; Forrest, A. R. R.; Standley, D. M.; Date, H.; Sakaguchi, S.; Forrest, A. R. R.; Kawaji, H.; Rehli, M.; Baillie, J. K.; de Hoon, M. J. L.; Haberle, V.; Lassmann, T.; Kulakovskiy, I. V.; Lizio, M.; Itoh, M.; Andersson, R.; Mungall, C. J.; Meehan, T. F.; Schmeier, S.; Bertin, N.; Jorgensen, M.; Dimont, E.; Arner, E.; Schmidl, C.; Schaefer, U.; Medvedeva, Y. A.; Plessy, C.; Vitezic, M.; Severin, J.; Semple, C. A.; Ishizu, Y.; Francescatto, M.; Alam, I.; Albanese, D.; Altschuler, G. M.; Archer, J. A. C.; Arner, P.; Babina, M.; Baker, S.; Balwierz, P. J.; Beckhouse, A. G.; Pradhan-Bhatt, S.; Blake, J. A.; Blumenthal, A.; Bodega, B.; Bonetti, A.; Briggs, J.; Brombacher, F.; Burroughs, A. M.; Califano, A.; Cannistraci, C. V.; Carbajo, D.; Chen, Y.; Chierici, M.; Ciani, Y.; Clevers, H. C.; Dalla, E.; Davis, C. A.; Deplancke, B.; Detmar, M.; Diehl, A. D.; Dohi, T.; Drablos, F.; Edge, A. S. B.; Edinger, M.; Ekwall, K.; Endoh, M.; Enomoto, H.; Fagiolini, M.; Fairbairn, L.; Fang, H.; Farach-Carson, M. C.; Faulkner, G. J.; Favorov, A. V.; Fisher, M. E.; Frith, M. C.; Fujita, R.; Fukuda, S.; Furlanello, C.; Furuno, M.; Furusawa, J. -i.; Geijtenbeek, T. B.; Gibson, A.; Gingeras, T.; Goldowitz, D.; Gough, J.; Guhl, S.; Guler, R.; Gustincich, S.; T. J., Ha; Hamaguchi, M.; Hara, M.; Harbers, M.; Harshbarger, J.; Hasegawa, A.; Hasegawa, Y.; Hashimoto, T.; Herlyn, M.; Hitchens, K. J.; Sui, S. J. H.; Hofmann, O. M.; Hoof, I.; Hori, F.; Huminiecki, L.; Iida, K.; Ikawa, T.; Jankovic, B. R.; Jia, H.; Joshi, A.; Jurman, G.; Kaczkowski, B.; Kai, C.; Kaida, K.; Kaiho, A.; Kajiyama, K.; Kanamori-Katayama, M.; Kasianov, A. S.; Kasukawa, T.; Katayama, S.; Kato, S.; Kawaguchi, S.; Kawamoto, H.; Kawamura, Y. I.; Kawashima, T.; Kempfle, J. S.; Kenna, T. J.; Kere, J.; Khachigian, L. M.; Kitamura, T.; Klinken, S. P.; Knox, A. J.; Kojima, M.; Kojima, S.; Kondo, N.; Koseki, H.; Koyasu, S.; Krampitz, S.; Kubosaki, A.; Kwon, A. T.; Laros, J. F. J.; Lee, W.; Lennartsson, A.; Li, K.; Lilje, B.; Lipovich, L.; Mackay-sim, A.; Manabe, R. -i.; Mar, J. C.; Marchand, B.; Mathelier, A.; Mejhert, N.; Meynert, A.; Mizuno, Y.; Morais, D. A. d. L.; Morikawa, H.; Morimoto, M.; Moro, K.; Motakis, E.; Motohashi, H.; Mummery, C. L.; Murata, M.; Nagao-Sato, S.; Nakachi, Y.; Nakahara, F.; Nakamura, T.; Nakamura, Y.; Nakazato, K.; van Nimwegen, E.; Ninomiya, N.; Nishiyori, H.; Noma, S.; Nozaki, T.; Ogishima, S.; Ohkura, N.; Ohmiya, H.; Ohno, H.; Ohshima, M.; Okada-Hatakeyama, M.; Okazaki, Y.; Orlando, V.; Ovchinnikov, D. A.; Pain, A.; Passier, R.; Patrikakis, M.; Persson, H.; Piazza, S.; Prendergast, J. G. D.; Rackham, O. J. L.; Ramilowski, J. A.; Rashid, M.; Ravasi, T.; Rizzu, P.; Roncador, M.; Roy, S.; Rye, M. B.; Saijyo, E.; Sajantila, A.; Saka, A.; Sakaguchi, S.; Sakai, M.; Sato, H.; Satoh, H.; Savvi, S.; Saxena, A.; Schneider, C.; Schultes, E. A.; Schulze-Tanzil, G. G.; Schwegmann, A.; Sengstag, T.; Sheng, G.; Shimoji, H.; Shimoni, Y.; Shin, J. W.; Simon, C.; Sugiyama, D.; Sugiyama, T.; Suzuki, M.; Swoboda, R. K.; Hoen, P. A. C. 't.; Tagami, M.; Takahashi, N.; Takai, J.; Tanaka, H.; Tatsukawa, H.; Tatum, Z.; Thompson, M.; Toyoda, H.; Toyoda, T.; Valen, E.; van de Wetering, M.; van den Berg, L. M.; Verardo, R.; Vijayan, D.; Vorontsov, I. E.; Wasserman, W. W.; Watanabe, S.; Wells, C. A.; Winteringham, L. N.; Wolvetang, E.; Wood, E. J.; Yamaguchi, Y.; Yamamoto, M.; Yoneda, M.; Yonekura, Y.; Yoshida, S.; Zabierowski, S. E.; Zhang, P. G.; Zhao, X.; Zucchelli, S.; Summers, K. M.; Suzuki, H.; Daub, C. O.; Kawai, J.; Heutink, P.; Hide, W.; Freeman, T. C.; Lenhard, B.; Bajic, V. B.; Taylor, M. S.; Makeev, V. J.; Sandelin, A.; Hume, D. A.; Carninci, P.; Hayashizaki, Y.

doi:10.1073/pnas.1312717110

Naturally occurring regulatory T (Treg) cells, which specifically express the transcription factor forkhead box P3 (Foxp3), are engaged in the maintenance of immunological self-tolerance and homeostasis. By transcriptional start site cluster analysis, we assessed here how genome-wide patterns of DNA methylation or Foxp3 binding sites were associated with Treg-specific gene expression. We found that Treg-specific DNA hypomethylated regions were closely associated with Treg up-regulated transcriptional start site clusters, whereas Foxp3 binding regions had no significant correlation with either up- or down-regulated clusters in nonactivated Treg cells. However, in activated Treg cells, Foxp3 binding regions showed a strong correlation with down-regulated clusters. In accordance with these findings, the above two features of activation-dependent gene regulation in Treg cells tend to occur at different locations in the genome. The results collectively indicate that Treg-specific DNA hypomethylation is instrumental in gene up-regulation in steady state Treg cells, whereas Foxp3 down-regulates the expression of its target genes in activated Treg cells. Thus, the two events seem to play distinct but complementary roles in Treg-specific gene expression.