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

Authors: Hiromasa Morikawa, Naganari Ohkura, Alexis Vandenbon, Masayoshi Itoh, Sayaka Nagao-Sato, Hideya Kawaji, Timo Lassmann, Piero Carninci, Yoshihide Hayashizaki, Alistair R. R. Forrest, Daron M. Standley, Hiroshi Date, Shimon Sakaguchi, Alistair R. R. Forrest, Hideya Kawaji, Michael Rehli, J. Kenneth Baillie, Michiel de Hoon, Vanja Haberle, Timo Lassmann, Ivan V. Kulakovskiy, Marina Lizio, Masayoshi Itoh, Robin Andersson, Chris Mungall, Terrence F. Meehan, Sebastian Schmeier, Nicolas Bertin, Mette Jørgensen, Emmanuel Dimont, Erik Arner, Christian Schmidl, Ulf Schaefer, Yulia A. Medvedeva, Charles Plessy, Morana Vitezic, Jessica Severin, Colin A. Semple, Yuri Ishizu, Margherita Francescatto, Intikhab Alam, Davide Albanese, Gabriel Altschuler, John A. C. Archer, Peter Arner, Magda Babina, Sarah Baker, Piotr J. Balwierz, Anthony G Beckhouse, Swati Pradhan-Bhatt, Judith A. Blake, Antje Blumenthal, Beatrice Bodega, Alessandro Bonetti, James Briggs, Frank Brombacher, A. Maxwell Burroughs, Andrea Califano, Carlo Vittorio Cannistraci, Daniel Carbajo, Yun Chen, Marco Chierici, Yari Ciani, Hans Clevers, Emiliano Dalla, Carrie Davis, Bart Deplancke, Michael Detmar, Alexander D. Diehl, Taeko Dohi, Finn Drabløs, Albert S.B. Edge, Matthias Edinger, Karl Ekwall, Mitsuhiro Endoh, Hideki Enomoto, Michela Fagiolini, Lynsey Fairbairn, Hai Fang, Mary C. Farach‐Carson, Geoffrey J. Faulkner, Alexander V. Favorov, Malcolm E Fisher, Martin C. Frith, Rie Fujita, Shiro Fukuda, Cesare Furlanello, Masaaki Furuno, Jun-ichi Furusawa, Teunis B. H. Geijtenbeek, Andrew Gibson, T Gingeras, Dan Goldowitz, Julian Gough, Sven Guhl, Reto Guler, Stefano Gustincich, Thomas J Ha, Masahide Hamaguchi, Mitsuko Hara, Matthias Harbers, Jayson Harshbarger, Akira Hasegawa, Yuki Hasegawa, Takehiro Hashimoto, Meenhard Herlyn, Kelly J Hitchens, Shannan J. Ho Sui, Oliver Hofmann, Ilka Hoof, Fumi Hori, Łukasz Huminiecki, Kei Iida, Tomokatsu Ikawa, Boris R. Janković, Hui Jia, Anagha Joshi, Giuseppe Jurman, Bogumił Kaczkowski, Chieko Kai, Kaoru Kaida, Ai Kaiho, Kazuhiro Kajiyama, Mutsumi Kanamori-Katayama, Artem S. Kasianov, Takeya Kasukawa, Shintaro Katayama, Sachi Kato, Shuji Kawaguchi, Hiroshi Kawamoto, Yuki I. Kawamura, Tsugumi Kawashima, Judith S. Kempfle, Tony Kenna, Juha Kere, Levon M. Khachigian, Toshio Kitamura, S. Peter Klinken, Alan J. Knox, Miki Kojima, Soichi Kojima, Naoto Kondo, Haruhiko Koseki, Shigeo Koyasu, Sarah Krampitz, Atsutaka Kubosaki, Andrew Tae-Jun Kwon, Jeroen F. J. Laros, Weon-Ju Lee, Andreas Lennartsson, Kang Li, Berit Lilje, Leonard Lipovich, Alan Mackay‐Sim, Ri‐Ichiroh Manabe, Jessica C. Mar, Benoı̂t Marchand, Anthony Mathelier, Niklas Mejhert, Alison Meynert, Yosuke Mizuno, David Anderson de Lima Morais, Hiromasa Morikawa, Mitsuru Morimoto, Kazuyo Moro, Efthymios Motakis, Hozumi Motohashi, Christine L. Mummery, Mitsuyoshi Murata, Sayaka Nagao-Sato, Yutaka Nakachi, Fumio Nakahara, Toshiyuki Nakamura, Yukio Nakamura, Kenichi Nakazato, Erik van Nimwegen, Noriko Ninomiya, Hiromi Nishiyori, Shohei Noma, Tadasuke Nozaki, Soichi Ogishima, Naganari Ohkura, Hiroko Ohmiya, Hiroshi Ohno, Mitsuhiro Ohshima, Mariko Okada, Yasushi Okazaki, Valerio Orlando, Dmitry A. Ovchinnikov, Arnab Pain, Robert Passier, Margaret Patrikakis, Helena Persson, Silvano Piazza, James Prendergast, Owen J. L. Rackham, Jordan A. Ramilowski, Mamoon Rashid, Timothy Ravasi, Patrizia Rizzu, Marco Roncador, Sugata Roy, Morten Beck Rye, Eri Saijyo, Antti Sajantila, Akiko Saka, Shimon Sakaguchi, Mizuho Sakai, Hiroki Sato, Hironori Satoh, Suzana Savvi, Alka Saxena, Claudio Schneider, Erik Schultes, Gundula Schulze‐Tanzil, Anita Schwegmann, Thierry Sengstag, Guojun Sheng, Hisashi Shimoji, Yishai Shimoni, Jay W. Shin, Christophe Simon, Daisuke Sugiyama, Takaaki Sugiyama, Masanori Suzuki, Rolf Swoboda, Peter A.C. ’t Hoen, Michihira Tagami, Takahashi Naoko, Jun Takai, Hiroshi Tanaka, Hideki Tatsukawa, Zuotian Tatum, Mark Thompson, Hiroo Toyoda, Tetsuro Toyoda, Eivind Valen, Marc van de Wetering, Linda Berg, Roberto Verardo, Dipti Vijayan, Ilya E. Vorontsov, Wyeth W. Wasserman, Shoko Watanabe, Christine A. Wells, Louise N Winteringham, Ernst J. Wolvetang, Emily J. Wood, Yoko Yamaguchi, Masayuki Yamamoto, Misako Yoneda, Yohei Yonekura, Shigehiro Yoshida, Suzan E. Zabierowski, Peter Zhang, Xiaobei Zhao, S. Zucchelli, Kim Summers, Harukazu Suzuki, Carsten O. Daub, Jun Kawai, Peter Heutink, Winston Hide, Tom C. Freeman, Boris Lenhard, Vladimir B. Bajić, Martin S. Taylor, Vsevolod J. Makeev, Albin Sandelin, David Hume, Piero Carninci, Yoshihide Hayashizaki - Proceedings of the National Academy of Sciences, PNAS 2014 cited by 138

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.