Differential roles of epigenetic changes and Foxp3 expression in regulatory T cell-specific transcriptional regulation
Authors: Morikawa Hiromasa , Ohkura Naganari , Vandenbon Alexis , Itoh Masayoshi , Nagao-Sato Sayaka , Kawaji Hideya , Lassmann Timo , Carninci Piero , Hayashizaki Yoshihide , Forrest Alistair R. R. , Standley Daron M. , Date Hiroshi , Sakaguchi Shimon ,   the FANTOM Consortium, Forrest Alistair R.R. , Kawaji Hideya , Rehli Michael , Baillie J. Kenneth , de Hoon Michiel J.L. , Haberle Vanja , Lassmann Timo , Kulakovskiy Ivan V. , Lizio Marina , Itoh Masayoshi , Andersson Robin , Mungall Christopher J. , Meehan Terrence F. , Schmeier Sebastian , Bertin Nicolas , Jørgensen Mette , Dimont Emmanuel , Arner Erik , Schmidl Christian , Schaefer Ulf , Medvedeva Yulia A. , Plessy Charles , Vitezic Morana , Severin Jessica , Semple Colin A. , Ishizu Yuri , Francescatto Margherita , Alam Intikhab , Albanese Davide , Altschuler Gabriel M. , Archer John A.C. , Arner Peter , Babina Magda , Baker Sarah , Balwierz Piotr J. , Beckhouse Anthony G. , Pradhan-Bhatt Swati , Blake Judith A. , Blumenthal Antje , Bodega Beatrice , Bonetti Alessandro , Briggs James , Brombacher Frank , Burroughs A. Maxwell , Califano Andrea , Cannistraci Carlo V. , Carbajo Daniel , Chen Yun , Chierici Marco , Ciani Yari , Clevers Hans C. , Dalla Emiliano , Davis Carrie A. , Deplancke Bart , Detmar Michael , Diehl Alexander D. , Dohi Taeko , Drabløs Finn , Edge Albert S.B. , Edinger Matthias , Ekwall Karl , Endoh Mitsuhiro , Enomoto Hideki , Fagiolini Michela , Fairbairn Lynsey , Fang Hai , Farach-Carson Mary C. , Faulkner Geoffrey J. , Favorov Alexander V. , Fisher Malcolm E. , Frith Martin C. , Fujita Rie , Fukuda Shiro , Furlanello Cesare , Furuno Masaaki , Furusawa Jun-ichi , Geijtenbeek Teunis B. , Gibson Andrew , Gingeras Thomas , Goldowitz Daniel , Gough Julian , Guhl Sven , Guler Reto , Gustincich Stefano , Ha Thomas J. , Hamaguchi Masahide , Hara Mitsuko , Harbers Matthias , Harshbarger Jayson , Hasegawa Akira , Hasegawa Yuki , Hashimoto Takehiro , Herlyn Meenhard , Hitchens Kelly J. , Sui Shannan J. Ho , Hofmann Oliver M. , Hoof Ilka , Hori Fumi , Huminiecki Lukasz , Iida Kei , Ikawa Tomokatsu , Jankovic Boris R. , Jia Hui , Joshi Anagha , Jurman Giuseppe , Kaczkowski Bogumil , Kai Chieko , Kaida Kaoru , Kaiho Ai , Kajiyama Kazuhiro , Kanamori-Katayama Mutsumi , Kasianov Artem S. , Kasukawa Takeya , Katayama Shintaro , Kato Sachi , Kawaguchi Shuji , Kawamoto Hiroshi , Kawamura Yuki I. , Kawashima Tsugumi , Kempfle Judith S. , Kenna Tony J. , Kere Juha , Khachigian Levon M. , Kitamura Toshio , Klinken S. Peter , Knox Alan J. , Kojima Miki , Kojima Soichi , Kondo Naoto , Koseki Haruhiko , Koyasu Shigeo , Krampitz Sarah , Kubosaki Atsutaka , Kwon Andrew T. , Laros Jeroen F.J. , Lee Weonju , Lennartsson Andreas , Li Kang , Lilje Berit , Lipovich Leonard , Mackay-sim Alan , Manabe Ri-ichiroh , Mar Jessica C. , Marchand Benoit , Mathelier Anthony , Mejhert Niklas , Meynert Alison , Mizuno Yosuke , Morais David A. de Lima , Morikawa Hiromasa , Morimoto Mitsuru , Moro Kazuyo , Motakis Efthymios , Motohashi Hozumi , Mummery Christine L. , Murata Mitsuyoshi , Nagao-Sato Sayaka , Nakachi Yutaka , Nakahara Fumio , Nakamura Toshiyuki , Nakamura Yukio , Nakazato Kenichi , van Nimwegen Erik , Ninomiya Noriko , Nishiyori Hiromi , Noma Shohei , Nozaki Tadasuke , Ogishima Soichi , Ohkura Naganari , Ohmiya Hiroko , Ohno Hiroshi , Ohshima Mitsuhiro , Okada-Hatakeyama Mariko , Okazaki Yasushi , Orlando Valerio , Ovchinnikov Dmitry A. , Pain Arnab , Passier Robert , Patrikakis Margaret , Persson Helena , Piazza Silvano , Prendergast James G.D. , Rackham Owen J.L. , Ramilowski Jordan A. , Rashid Mamoon , Ravasi Timothy , Rizzu Patrizia , Roncador Marco , Roy Sugata , Rye Morten B. , Saijyo Eri , Sajantila Antti , Saka Akiko , Sakaguchi Shimon , Sakai Mizuho , Sato Hiroki , Satoh Hironori , Savvi Suzana , Saxena Alka , Schneider Claudio , Schultes Erik A. , Schulze-Tanzil Gundula G. , Schwegmann Anita , Sengstag Thierry , Sheng Guojun , Shimoji Hisashi , Shimoni Yishai , Shin Jay W. , Simon Christophe , Sugiyama Daisuke , Sugiyama Takaaki , Suzuki Masanori , Swoboda Rolf K. , 't Hoen Peter A.C. , Tagami Michihira , Takahashi Naoko , Takai Jun , Tanaka Hiroshi , Tatsukawa Hideki , Tatum Zuotian , Thompson Mark , Toyoda Hiroo , Toyoda Tetsuro , Valen Eivind , van de Wetering Marc , van den Berg Linda M. , Verardo Roberto , Vijayan Dipti , Vorontsov Ilya E. , Wasserman Wyeth W. , Watanabe Shoko , Wells Christine A. , Winteringham Louise N. , Wolvetang Ernst , Wood Emily J. , Yamaguchi Yoko , Yamamoto Masayuki , Yoneda Misako , Yonekura Yohei , Yoshida Shigehiro , Zabierowski Suzan E. , Zhang Peter G. , Zhao Xiaobei , Zucchelli Silvia , Summers Kim M. , Suzuki Harukazu , Daub Carsten O. , Kawai Jun , Heutink Peter , Hide Winston , Freeman Tom C. , Lenhard Boris , Bajic Vladimir B. , Taylor Martin S. , Makeev Vsevolod J. , Sandelin Albin , Hume David A. , Carninci Piero , Hayashizaki Yoshihide 
Published: March 2014

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.