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56. Enzymatic Activity of HPGD in Treg Cells Suppresses Tconv Cells to Maintain Adipose Tissue Homeostasis and Prevent Metabolic Dysfunction

Author

Schmidleithner, Lisa, Thabet, Yasser, Schoenfeld, Eva, Koehne, Maren, Sommer, Daniel, Abdullah, Zeinab, Sadlon, Timothy, Osei-Sarpong, Collins, Subbaramaiah, Kotha, Copperi, Francesca, Haendler, Kristian, Varga, Tamas, Schanz, Oliver, Bourry, Svenja, Bassler, Kevin, Krebs, Wolfgang, Peters, Annika E., Baumgart, Ann-Kathrin, Schneeweiss, Maria, Klee, Kathrin, Schmidt, Susanne V., Nuessing, Simone, Sander, Jil, Ohkura, Naganari, Waha, Andreas, Sparwasser, Tim, Wunderlich, F. Thomas, Foerster, Irmgard, Ulas, Thomas, Weighardt, Heike, Sakaguchi, Shimon, Pfeifer, Alexander, Blueher, Matthias, Dannenberg, Andrew J., Ferreiros, Nerea, Muglia, Louis J., Wickenhauser, Claudia, Barry, Simon C., Schultze, Joachim L., Beyer, Marc, Schmidleithner, Lisa, Thabet, Yasser, Schoenfeld, Eva, Koehne, Maren, Sommer, Daniel, Abdullah, Zeinab, Sadlon, Timothy, Osei-Sarpong, Collins, Subbaramaiah, Kotha, Copperi, Francesca, Haendler, Kristian, Varga, Tamas, Schanz, Oliver, Bourry, Svenja, Bassler, Kevin, Krebs, Wolfgang, Peters, Annika E., Baumgart, Ann-Kathrin, Schneeweiss, Maria, Klee, Kathrin, Schmidt, Susanne V., Nuessing, Simone, Sander, Jil, Ohkura, Naganari, Waha, Andreas, Sparwasser, Tim, Wunderlich, F. Thomas, Foerster, Irmgard, Ulas, Thomas, Weighardt, Heike, Sakaguchi, Shimon, Pfeifer, Alexander, Blueher, Matthias, Dannenberg, Andrew J., Ferreiros, Nerea, Muglia, Louis J., Wickenhauser, Claudia, Barry, Simon C., Schultze, Joachim L., and Beyer, Marc

Abstract

Regulatory T cells (Treg cells) are important for preventing autoimmunity and maintaining tissue homeostasis, but whether Treg cells can adopt tissue- or immune-context-specific suppressive mechanisms is unclear. Here, we found that the enzyme hydroxyprostaglandin dehydrogenase (HPGD), which catabolizes prostaglandin E-2 (PGE(2)) into the metabolite 15-keto PGE(2), was highly expressed in Treg cells, particularly those in visceral adipose tissue (VAT). Nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR gamma)-induced HPGD expression in VAT Treg cells, and consequential Treg-cell-mediated generation of 15-keto PG E2 suppressed conventional T cell activation and proliferation. Conditional deletion of Hpgd in mouse Treg cells resulted in the accumulation of functionally impaired Treg cells specifically in VAT, causing local inflammation and systemic insulin resistance. Consistent with this mechanism, humans with type 2 diabetes showed decreased HPGD expression in Treg cells. These data indicate that HPGD-mediated suppression is a tissue- and context-dependent suppressive mechanism used by Treg cells to maintain adipose tissue homeostasis.

Published
2019

57. Regulatory roles of IL-10 – producing human follicular T cells

Author

F Canete, Pablo, Sweet, Rebecca, Gonzalez-Figueroa, Paula, Papa, Ilenia, Ohkura, Naganari, Bolton, Holly, Roco Alegre, Jonathan, Cuenca, Marta, Bassett, Katharine, Sayin, Ismail, Barry, E, Lopez, Angel F., Canaday, David H, Meyer-Hermann, Michael, Doglioni, Claudio, Fazekas de St Groth, Barbara, Sakaguchi, Shimon, Prof, Cook, Matthew, Vinuesa, Carola, F Canete, Pablo, Sweet, Rebecca, Gonzalez-Figueroa, Paula, Papa, Ilenia, Ohkura, Naganari, Bolton, Holly, Roco Alegre, Jonathan, Cuenca, Marta, Bassett, Katharine, Sayin, Ismail, Barry, E, Lopez, Angel F., Canaday, David H, Meyer-Hermann, Michael, Doglioni, Claudio, Fazekas de St Groth, Barbara, Sakaguchi, Shimon, Prof, Cook, Matthew, and Vinuesa, Carola

Abstract

Mucosal lymphoid tissues such as human tonsil are colonized by bacteria and exposed to ingested and inhaled antigens, requiring tight regulation of immune responses. Antibody responses are regulated by follicular helper T (TFH) cells and FOXP3+ follicular regulatory T (TFR) cells. Here we describe a subset of human tonsillar follicular T cells identified by expression of TFH markers and CD25 that are the main source of follicular T (TF) cell–derived IL-10. Despite lack of FOXP3 expression, CD25+ TF cells resemble T reg cells in high CTLA4 expression, low IL-2 production, and their ability to repress T cell proliferation. CD25+ TF cell–derived IL-10 dampens induction of B cell class-switching to IgE. In children, circulating total IgE titers were inversely correlated with the frequencies of tonsil CD25+ TF cells and IL-10–producing TF cells but not with total T reg cells, TFR, or IL-10–producing T cells. Thus, CD25+ TF cells emerge as a subset with unique T and B cell regulatory activities that may help prevent atopy

Published
2019

58. Conversion of antigen-specific effector/memory T cells into Foxp3-expressing T reg cells by inhibition of CDK8/19

Author

Akamatsu, Masahiko, primary, Mikami, Norihisa, additional, Ohkura, Naganari, additional, Kawakami, Ryoji, additional, Kitagawa, Yohko, additional, Sugimoto, Atsushi, additional, Hirota, Keiji, additional, Nakamura, Naoto, additional, Ujihara, Satoru, additional, Kurosaki, Toshio, additional, Hamaguchi, Hisao, additional, Harada, Hironori, additional, Xia, Guliang, additional, Morita, Yoshiaki, additional, Aramori, Ichiro, additional, Narumiya, Shuh, additional, and Sakaguchi, Shimon, additional

Published
2019
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60. The tumor-infiltrating effector regulatory T cell:CD8+ lymphocyte ratio in invasive breast cancer

Author

Okada, Morihito, primary, Goda, Noriko, additional, Sasada, Shinsuke, additional, Shigematsu, Hideo, additional, Masumoto, Norio, additional, Shiroma, Noriyuki, additional, Arihiro, Koji, additional, Kadoya, Takayuki, additional, Kidani, Yujiro, additional, Ohkura, Naganari, additional, Nishikawa, Hiroyoshi, additional, and Sakaguchi, Shimon, additional

Published
2019
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61. Regulatory roles of IL-10–producing human follicular T cells

Author

Cañete, Pablo F., primary, Sweet, Rebecca A., additional, Gonzalez-Figueroa, Paula, additional, Papa, Ilenia, additional, Ohkura, Naganari, additional, Bolton, Holly, additional, Roco, Jonathan A., additional, Cuenca, Marta, additional, Bassett, Katharine J., additional, Sayin, Ismail, additional, Barry, Emma, additional, Lopez, Angel, additional, Canaday, David H., additional, Meyer-Hermann, Michael, additional, Doglioni, Claudio, additional, Fazekas de St Groth, Barbara, additional, Sakaguchi, Shimon, additional, Cook, Matthew C., additional, and Vinuesa, Carola G., additional

Published
2019
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63. Enzymatic Activity of HPGD in Treg Cells Suppresses Tconv Cells to Maintain Adipose Tissue Homeostasis and Prevent Metabolic Dysfunction

Author

Schmidleithner, Lisa, primary, Thabet, Yasser, additional, Schönfeld, Eva, additional, Köhne, Maren, additional, Sommer, Daniel, additional, Abdullah, Zeinab, additional, Sadlon, Timothy, additional, Osei-Sarpong, Collins, additional, Subbaramaiah, Kotha, additional, Copperi, Francesca, additional, Haendler, Kristian, additional, Varga, Tamas, additional, Schanz, Oliver, additional, Bourry, Svenja, additional, Bassler, Kevin, additional, Krebs, Wolfgang, additional, Peters, Annika E., additional, Baumgart, Ann-Kathrin, additional, Schneeweiss, Maria, additional, Klee, Kathrin, additional, Schmidt, Susanne V., additional, Nüssing, Simone, additional, Sander, Jil, additional, Ohkura, Naganari, additional, Waha, Andreas, additional, Sparwasser, Tim, additional, Wunderlich, F. Thomas, additional, Förster, Irmgard, additional, Ulas, Thomas, additional, Weighardt, Heike, additional, Sakaguchi, Shimon, additional, Pfeifer, Alexander, additional, Blüher, Matthias, additional, Dannenberg, Andrew J., additional, Ferreirós, Nerea, additional, Muglia, Louis J., additional, Wickenhauser, Claudia, additional, Barry, Simon C., additional, Schultze, Joachim L., additional, and Beyer, Marc, additional

Published
2019
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64. Loss of TET proteins in regulatory T cells promotes abnormal proliferation, Foxp3 destabilization and IL-17 expression

Author

Nakatsukasa, Hiroko, primary, Oda, Mayumi, additional, Yin, Jinghua, additional, Chikuma, Shunsuke, additional, Ito, Minako, additional, Koga-Iizuka, Mana, additional, Someya, Kazue, additional, Kitagawa, Yohko, additional, Ohkura, Naganari, additional, Sakaguchi, Shimon, additional, Koya, Ikuko, additional, Sanosaka, Tsukasa, additional, Kohyama, Jun, additional, Tsukada, Yu-ichi, additional, Yamanaka, Soichiro, additional, Takamura-Enya, Takeji, additional, Lu, Qianjin, additional, and Yoshimura, Akihiko, additional

Published
2019
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66. Data Descriptor : FANTOM5 CAGE profiles of human and mouse samples

Author

Noguchi, Shuhei, Arakawa, Takahiro, Fukuda, Shiro, Furuno, Masaaki, Hasegawa, Akira, Hori, Fumi, Ishikawa-Kato, Sachi, Kaida, Kaoru, Kaiho, Ai, Kanamori-Katayama, Mutsumi, Kawashima, Tsugumi, Kojima, Miki, Kubosaki, Atsutaka, Manabe, Ri-ichiroh, Murata, Mitsuyoshi, Nagao-Sato, Sayaka, Nakazato, Kenichi, Ninomiya, Noriko, Nishiyori-Sueki, Hiromi, Noma, Shohei, Saijyo, Eri, Saka, Akiko, Sakai, Mizuho, Simon, Christophe, Suzuki, Naoko, Tagami, Michihira, Watanabe, Shoko, Yoshida, Shigehiro, Arner, Peter, Axton, Richard A., Babina, Magda, Baillie, J. Kenneth, Barnett, Timothy C., Beckhouse, Anthony G., Blumenthal, Antje, Bodega, Beatrice, Bonetti, Alessandro, Briggs, James, Brombacher, Frank, Carlisle, Ailsa J., Clevers, Hans C., Davis, Carrie A., Detmar, Michael, Dohi, Taeko, Edge, Albert S. B., Edinger, Matthias, Ehrlund, Anna, Ekwall, Karl, Endoh, Mitsuhiro, Enomoto, Hideki, Eslami, Afsaneh, Fagiolini, Michela, Fairbairn, Lynsey, Farach-Carson, Mary C., Faulkner, Geoffrey J., Ferrai, Carmelo, Fisher, Malcolm E., Forrester, Lesley M., Fujita, Rie, Furusawa, Jun-ichi, Geijtenbeek, Teunis B., Gingeras, Thomas, Goldowitz, Daniel, Guhl, Sven, Guler, Reto, Gustincich, Stefano, Ha, Thomas J., Hamaguchi, Masahide, Hara, Mitsuko, Hasegawa, Yuki, Herlyn, Meenhard, Heutink, Peter, Hitchens, Kelly J., Hume, David A., Ikawa, Tomokatsu, Ishizu, Yuri, Kai, Chieko, Kawamoto, Hiroshi, Kawamura, Yuki I., Kempfle, Judith S., Kenna, Tony J., Kere, Juha, Khachigian, Levon M., Kitamura, Toshio, Klein, Sarah, Klinken, S. Peter, Knox, Alan J., Kojima, Soichi, Koseki, Haruhiko, Koyasu, Shigeo, Lee, Weonju, Lennartsson, Andreas, Mackay-sim, Alan, Mejhert, Niklas, Mizuno, Yosuke, Morikawa, Hiromasa, Morimoto, Mitsuru, Moro, Kazuyo, Morris, Kelly J., Motohashi, Hozumi, Mummery, Christine L., Nakachi, Yutaka, Nakahara, Fumio, Nakamura, Toshiyuki, Nakamura, Yukio, Nozaki, Tadasuke, Ogishima, Soichi, Ohkura, Naganari, Ohno, Hiroshi, Ohshima, Mitsuhiro, Okada-Hatakeyama, Mariko, Okazaki, Yasushi, Orlando, Valerio, Ovchinnikov, Dmitry A., Passier, Robert, Patrikakis, Margaret, Pombo, Ana, Pradhan-Bhatt, Swati, Qin, Xian-Yang, Rehli, Michael, Rizzu, Patrizia, Roy, Sugata, Sajantila, Antti, Sakaguchi, Shimon, Sato, Hiroki, Satoh, Hironori, Savvi, Suzana, Saxena, Alka, Schmidl, Christian, Schneider, Claudio, Schulze-Tanzil, Gundula G., Schwegmann, Anita, Sheng, Guojun, Shin, Jay W., Sugiyama, Daisuke, Sugiyama, Takaaki, Summers, Kim M., Takahashi, Naoko, Takai, Jun, Tanaka, Hiroshi, Tatsukawa, Hideki, Tomoiu, Andru, Toyoda, Hiroo, van de Wetering, Marc, van den Berg, Linda M., Verardo, Roberto, Vijayan, Dipti, Wells, Christine A., Winteringham, Louise N., Wolvetang, Ernst, Yamaguchi, Yoko, Yamamoto, Masayuki, Yanagi-Mizuochi, Chiyo, Yoneda, Misako, Yonekura, Yohei, Zhang, Peter G., Zucchelli, Silvia, Abugessaisa, Imad, Arner, Erik, Harshbarger, Jayson, Kondo, Atsushi, Lassmann, Timo, Lizio, Marina, Sahin, Serkan, Sengstag, Thierry, Severin, Jessica, Shimoji, Hisashi, Suzuki, Masanori, Suzuki, Harukazu, Kawai, Jun, Kondo, Naoto, Itoh, Masayoshi, Daub, Carsten O., Kasukawa, Takeya, Kawaji, Hideya, Carninci, Piero, Forrest, Alistair R. R., Hayashizaki, Yoshihide, Medicum, University of Helsinki, Forensic Medicine, Department of Forensic Medicine, and PaleOmics Laboratory

Subjects
ENHANCERS, MAMMALIAN-CELLS, UCSC GENOME BROWSER, VISUALIZATION, UPDATE, GROWTH, IN-VITRO, TRANSCRIPTION, 3111 Biomedicine, ATLAS, GENE-EXPRESSION
Abstract

In the FANTOM5 project, transcription initiation events across the human and mouse genomes were mapped at a single base-pair resolution and their frequencies were monitored by CAGE (Cap Analysis of Gene Expression) coupled with single-molecule sequencing. Approximately three thousands of samples, consisting of a variety of primary cells, tissues, cell lines, and time series samples during cell activation and development, were subjected to a uniform pipeline of CAGE data production. The analysis pipeline started by measuring RNA extracts to assess their quality, and continued to CAGE library production by using a robotic or a manual workflow, single molecule sequencing, and computational processing to generate frequencies of transcription initiation. Resulting data represents the consequence of transcriptional regulation in each analyzed state of mammalian cells. Non-overlapping peaks over the CAGE profiles, approximately 200,000 and 150,000 peaks for the human and mouse genomes, were identified and annotated to provide precise location of known promoters as well as novel ones, and to quantify their activities.

Published
2017

68. Clinical importance of the expression of CD4+CD8+ T cells in renal cell carcinoma.

Author

Nishida, Kentaro, Kawashima, Atsunari, Kanazawa, Takayuki, Kidani, Yujiro, Yoshida, Tetsuya, Hirata, Michinari, Yamamoto, Kei, Yamamoto, Yoko, Sawada, Masaaki, Kato, Ryo, Kato, Taigo, Hatano, Koji, Ujike, Takeshi, Fujita, Kazutoshi, Uemura, Motohide, Morimoto-Okazawa, Akiko, Iwahori, Kota, Yamasaki, Makoto, Ohkura, Naganari, and Sakaguchi, Shimon

Subjects
T cells, RENAL cell carcinoma, RNA sequencing, T cell receptors
Abstract

Objective CD4+CD8+ T cells are expressed in some cancer patients including those with renal cell carcinoma (RCC). However, no reports have mentioned the clinical importance of this expression. We evaluated the expression of CD4+CD8+ T cells in patients with various cancer types to clarify clinical characteristics and prognostic importance significantly correlating with these T cells. Methods Expression of CD4+CD8+ T cells was evaluated using flowcytometry in tissue-infiltrating lymphocytes extracted from 260 cancer tissues including 104 RCC samples. RNA sequencing and characterization and regression (Citrus) was used to determine characteristics. The prognostic importance of CD4+CD8+ T cells was evaluated by Cox regression analysis. Results Among eight cancer types, expression of CD4+CD8+ T cells was significantly highest in RCC patients. According to the expression of CD4+CD8+ T cells in adjacent normal tissue-infiltrating lymphocytes, 24 patients (23.1%) were defined as being positive for CD4+CD8+ with an expression higher than 9.29% in RCC patients. Citrus showed CD8+PD-1+TIM-3+CD103− T cells to be a specific subpopulation of CD4+CD8+ T cells. RNA sequencing revealed that CD4+CD8+ T cells had significantly lower diversity than the other T cells and shared most T-cell receptor clones with CD8+ not CD4+ T cells. Expression of CD4+CD8+ T cells was identified as an independent predictor of overall survival (hazard ratio: 0.11, 95% confidence interval: 0.01–0.86, P = 0.035) in multivariate analysis. Conclusions The expression of CD4+CD8+ T cells was significantly up-regulated in RCC patients and correlated significantly with prognostic importance in surgically treated RCC patients. [ABSTRACT FROM AUTHOR]

Published
2020
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69. Innate Myeloid Cell Subset-Specific Gene Expression Patterns in the Human Colon are Altered in Crohn’s Disease Patients

Author

Sekido, Yuki, primary, Yasumizu, Yoshiaki, additional, Nishimura, Junichi, additional, Kayama, Hisako, additional, Matsuno, Hiroshi, additional, Ogino, Takayuki, additional, Miyoshi, Norikatsu, additional, Takahashi, Hidekazu, additional, Haraguchi, Naotsugu, additional, Hata, Taishi, additional, Matsuda, Chu, additional, Doki, Yuichiro, additional, Mori, Masaki, additional, Takeda, Kiyoshi, additional, Ohkura, Naganari, additional, Sakaguchi, Shimon, additional, and Mizushima, Tsunekazu, additional

Published
2018
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70. Ultraviolet B–Induced Maturation of CD11b-Type Langerin− Dendritic Cells Controls the Expansion of Foxp3+ Regulatory T Cells in the Skin

Author

Yamazaki, Sayuri, primary, Odanaka, Mizuyu, additional, Nishioka, Akiko, additional, Kasuya, Saori, additional, Shime, Hiroaki, additional, Hemmi, Hiroaki, additional, Imai, Masaki, additional, Riethmacher, Dieter, additional, Kaisho, Tsuneyasu, additional, Ohkura, Naganari, additional, Sakaguchi, Shimon, additional, and Morita, Akimichi, additional

Published
2018
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71. FANTOM5 CAGE profiles of human and mouse samples

Author

Noguchi, Shuhei, Arakawa, Takahiro, Fukuda, Shiro, Furuno, Masaaki, Hasegawa, Akira, Hori, Fumi, Ishikawa-Kato, Sachi, Kaida, Kaoru, Kaiho, Ai, Kanamori-Katayama, Mutsumi, Kawashima, Tsugumi, Kojima, Miki, Kubosaki, Atsutaka, Manabe, Ri-ichiroh, Murata, Mitsuyoshi, Nagao-Sato, Sayaka, Nakazato, Kenichi, Ninomiya, Noriko, Nishiyori-Sueki, Hiromi, Noma, Shohei, Saijyo, Eri, Saka, Akiko, Sakai, Mizuho, Simon, Christophe, Suzuki, Naoko, Tagami, Michihira, Watanabe, Shoko, Yoshida, Shigehiro, Arner, Peter, Axton, Richard A, Babina, Magda, Baillie, J Kenneth, Barnett, Timothy C, Beckhouse, Anthony G, Blumenthal, Antje, Bodega, Beatrice, Bonetti, Alessandro, Briggs, James, Brombacher, Frank, Carlisle, Ailsa J, Clevers, Hans C, Davis, Carrie A, Detmar, Michael, Dohi, Taeko, Edge, Albert S B, Edinger, Matthias, Ehrlund, Anna, Ekwall, Karl, Endoh, Mitsuhiro, Enomoto, Hideki, Eslami, Afsaneh, Fagiolini, Michela, Fairbairn, Lynsey, Farach-Carson, Mary C, Faulkner, Geoffrey J, Ferrai, Carmelo, Fisher, Malcolm E, Forrester, Lesley M, Fujita, Rie, Furusawa, Jun-ichi, Geijtenbeek, Teunis B, Gingeras, Thomas, Goldowitz, Daniel, Guhl, Sven, Guler, Reto, Gustincich, Stefano, Ha, Thomas J, Hamaguchi, Masahide, Hara, Mitsuko, Hasegawa, Yuki, Herlyn, Meenhard, Heutink, Peter, Hitchens, Kelly J, Hume, David A, Ikawa, Tomokatsu, Ishizu, Yuri, Kai, Chieko, Kawamoto, Hiroshi, Kawamura, Yuki I, Kempfle, Judith S, Kenna, Tony J, Kere, Juha, Khachigian, Levon M, Kitamura, Toshio, Klein, Sarah, Klinken, S Peter, Knox, Alan J, Kojima, Soichi, Koseki, Haruhiko, Koyasu, Shigeo, Lee, Weonju, Lennartsson, Andreas, Mackay-Sim, Alan, Mejhert, Niklas, Mizuno, Yosuke, Morikawa, Hiromasa, Morimoto, Mitsuru, Moro, Kazuyo, Morris, Kelly J, Motohashi, Hozumi, Mummery, Christine L, Nakachi, Yutaka, Nakahara, Fumio, Nakamura, Toshiyuki, Nakamura, Yukio, Nozaki, Tadasuke, Ogishima, Soichi, Ohkura, Naganari, Ohno, Hiroshi, Ohshima, Mitsuhiro, Okada-Hatakeyama, Mariko, Okazaki, Yasushi, Orlando, Valerio, Ovchinnikov, Dmitry A, Passier, Robert, Patrikakis, Margaret, Pombo, Ana, Pradhan-Bhatt, Swati, Qin, Xian-Yang, Rehli, Michael, Rizzu, Patrizia, Roy, Sugata, Sajantila, Antti, Sakaguchi, Shimon, Sato, Hiroki, Satoh, Hironori, Savvi, Suzana, Saxena, Alka, Schmidl, Christian, Schneider, Claudio, Schulze-Tanzil, Gundula G, Schwegmann, Anita, Sheng, Guojun, Shin, Jay W, Sugiyama, Daisuke, Sugiyama, Takaaki, Summers, Kim M, Takahashi, Naoko, Takai, Jun, Tanaka, Hiroshi, Tatsukawa, Hideki, Tomoiu, Andru, Toyoda, Hiroo, van de Wetering, Marc, van den Berg, Linda M, Verardo, Roberto, Vijayan, Dipti, Wells, Christine A, Winteringham, Louise N, Wolvetang, Ernst, Yamaguchi, Yoko, Yamamoto, Masayuki, Yanagi-Mizuochi, Chiyo, Yoneda, Misako, Yonekura, Yohei, Zhang, Peter G, Zucchelli, Silvia, Abugessaisa, Imad, Arner, Erik, Harshbarger, Jayson, Kondo, Atsushi, Lassmann, Timo, Lizio, Marina, Sahin, Serkan, Sengstag, Thierry, Severin, Jessica, Shimoji, Hisashi, Suzuki, Masanori, Suzuki, Harukazu, Kawai, Jun, Kondo, Naoto, Itoh, Masayoshi, Daub, Carsten O, Kasukawa, Takeya, Kawaji, Hideya, Carninci, Piero, Forrest, Alistair R R, Hayashizaki, Yoshihide, Noguchi, Shuhei, Arakawa, Takahiro, Fukuda, Shiro, Furuno, Masaaki, Hasegawa, Akira, Hori, Fumi, Ishikawa-Kato, Sachi, Kaida, Kaoru, Kaiho, Ai, Kanamori-Katayama, Mutsumi, Kawashima, Tsugumi, Kojima, Miki, Kubosaki, Atsutaka, Manabe, Ri-ichiroh, Murata, Mitsuyoshi, Nagao-Sato, Sayaka, Nakazato, Kenichi, Ninomiya, Noriko, Nishiyori-Sueki, Hiromi, Noma, Shohei, Saijyo, Eri, Saka, Akiko, Sakai, Mizuho, Simon, Christophe, Suzuki, Naoko, Tagami, Michihira, Watanabe, Shoko, Yoshida, Shigehiro, Arner, Peter, Axton, Richard A, Babina, Magda, Baillie, J Kenneth, Barnett, Timothy C, Beckhouse, Anthony G, Blumenthal, Antje, Bodega, Beatrice, Bonetti, Alessandro, Briggs, James, Brombacher, Frank, Carlisle, Ailsa J, Clevers, Hans C, Davis, Carrie A, Detmar, Michael, Dohi, Taeko, Edge, Albert S B, Edinger, Matthias, Ehrlund, Anna, Ekwall, Karl, Endoh, Mitsuhiro, Enomoto, Hideki, Eslami, Afsaneh, Fagiolini, Michela, Fairbairn, Lynsey, Farach-Carson, Mary C, Faulkner, Geoffrey J, Ferrai, Carmelo, Fisher, Malcolm E, Forrester, Lesley M, Fujita, Rie, Furusawa, Jun-ichi, Geijtenbeek, Teunis B, Gingeras, Thomas, Goldowitz, Daniel, Guhl, Sven, Guler, Reto, Gustincich, Stefano, Ha, Thomas J, Hamaguchi, Masahide, Hara, Mitsuko, Hasegawa, Yuki, Herlyn, Meenhard, Heutink, Peter, Hitchens, Kelly J, Hume, David A, Ikawa, Tomokatsu, Ishizu, Yuri, Kai, Chieko, Kawamoto, Hiroshi, Kawamura, Yuki I, Kempfle, Judith S, Kenna, Tony J, Kere, Juha, Khachigian, Levon M, Kitamura, Toshio, Klein, Sarah, Klinken, S Peter, Knox, Alan J, Kojima, Soichi, Koseki, Haruhiko, Koyasu, Shigeo, Lee, Weonju, Lennartsson, Andreas, Mackay-Sim, Alan, Mejhert, Niklas, Mizuno, Yosuke, Morikawa, Hiromasa, Morimoto, Mitsuru, Moro, Kazuyo, Morris, Kelly J, Motohashi, Hozumi, Mummery, Christine L, Nakachi, Yutaka, Nakahara, Fumio, Nakamura, Toshiyuki, Nakamura, Yukio, Nozaki, Tadasuke, Ogishima, Soichi, Ohkura, Naganari, Ohno, Hiroshi, Ohshima, Mitsuhiro, Okada-Hatakeyama, Mariko, Okazaki, Yasushi, Orlando, Valerio, Ovchinnikov, Dmitry A, Passier, Robert, Patrikakis, Margaret, Pombo, Ana, Pradhan-Bhatt, Swati, Qin, Xian-Yang, Rehli, Michael, Rizzu, Patrizia, Roy, Sugata, Sajantila, Antti, Sakaguchi, Shimon, Sato, Hiroki, Satoh, Hironori, Savvi, Suzana, Saxena, Alka, Schmidl, Christian, Schneider, Claudio, Schulze-Tanzil, Gundula G, Schwegmann, Anita, Sheng, Guojun, Shin, Jay W, Sugiyama, Daisuke, Sugiyama, Takaaki, Summers, Kim M, Takahashi, Naoko, Takai, Jun, Tanaka, Hiroshi, Tatsukawa, Hideki, Tomoiu, Andru, Toyoda, Hiroo, van de Wetering, Marc, van den Berg, Linda M, Verardo, Roberto, Vijayan, Dipti, Wells, Christine A, Winteringham, Louise N, Wolvetang, Ernst, Yamaguchi, Yoko, Yamamoto, Masayuki, Yanagi-Mizuochi, Chiyo, Yoneda, Misako, Yonekura, Yohei, Zhang, Peter G, Zucchelli, Silvia, Abugessaisa, Imad, Arner, Erik, Harshbarger, Jayson, Kondo, Atsushi, Lassmann, Timo, Lizio, Marina, Sahin, Serkan, Sengstag, Thierry, Severin, Jessica, Shimoji, Hisashi, Suzuki, Masanori, Suzuki, Harukazu, Kawai, Jun, Kondo, Naoto, Itoh, Masayoshi, Daub, Carsten O, Kasukawa, Takeya, Kawaji, Hideya, Carninci, Piero, Forrest, Alistair R R, and Hayashizaki, Yoshihide

Abstract

In the FANTOM5 project, transcription initiation events across the human and mouse genomes were mapped at a single base-pair resolution and their frequencies were monitored by CAGE (Cap Analysis of Gene Expression) coupled with single-molecule sequencing. Approximately three thousands of samples, consisting of a variety of primary cells, tissues, cell lines, and time series samples during cell activation and development, were subjected to a uniform pipeline of CAGE data production. The analysis pipeline started by measuring RNA extracts to assess their quality, and continued to CAGE library production by using a robotic or a manual workflow, single molecule sequencing, and computational processing to generate frequencies of transcription initiation. Resulting data represents the consequence of transcriptional regulation in each analyzed state of mammalian cells. Non-overlapping peaks over the CAGE profiles, approximately 200,000 and 150,000 peaks for the human and mouse genomes, were identified and annotated to provide precise location of known promoters as well as novel ones, and to quantify their activities.

Published
2017

72. The Constrained Maximal Expression Level Owing to Haploidy Shapes Gene Content on the Mammalian X Chromosome

Author

Hurst, Laurence D., Ghanbarian, Avazeh T., Forrest, Alistair R R, Huminiecki, Lukasz, Rehli, Michael, Kenneth Baillie, J., 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, Young, Robert S., Francescatto, Margherita, Alam, Intikhab, Albanese, Davide, Altschuler, Gabriel M., Arakawa, Takahiro, Archer, John A C, Arner, Peter, Babina, Magda, Baker, Sarah, Balwierz, Piotr J., Beckhouse, Anthony G., Pradhan, Swati Bhatt, Blake, Judith A., Blumenthal, Antje, Bodega, Beatrice, Bonetti, Alessandro, Briggs, James, Brombacher, Frank, Maxwell Burroughs, A., Califano, Andrea, Cannistraci, Carlo V., Carbajo, Daniel, Chen, Yun, Chierici, Marco, Ciani, Yari, Clevers, Hans C., Dalla, Emiliano, Davis, Carrie A., 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., Ho Sui, Shannan J., Hofmann, Oliver M., Hoof, Ilka, Hori, Fumi, Iida, Kei, Ikawa, Tomokatsu, Jankovic, Boris R., Jia, Hui, Joshi, Anagha, Jurman, Giuseppe, Kaczkowski, Bogumil, Kai, Chieko, Kaida, Kaoru, Kaiho, Ai, Kajiyama, Kazuhiro, Kanamori, Mutsumi Katayama, 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, Peter Klinken, S., 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, Alan sim, Manabe, Riichiroh, Mar, Jessica C., Marchand, Benoit, Mathelier, Anthony, Mejhert, Niklas, Meynert, Alison, Mizuno, Yosuke, de Lima Morais, David A., Morikawa, Hiromasa, Morimoto, Mitsuru, Moro, Kazuyo, Motakis, Efthymios, Motohashi, Hozumi, Mummery, Christine L., Murata, Mitsuyoshi, Nagao, Sayaka Sato, 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, Mariko Hatakeyama, 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, Suzuki, Naoko, 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 Gustav, Hume, David A., Carninci, Piero, Hayashizaki, Yoshihide, Hubrecht Institute for Developmental Biology and Stem Cell Research, Barton, Nick H, Amsterdam institute for Infection and Immunity, Infectious diseases, and Experimental Immunology

Subjects
Male, Medical and Health Sciences, Essential, Models, Gene expression, Databases, Genetic, Biology (General), Non-U.S. Gov't, X-linked recessive inheritance, X chromosome, Cells, Cultured, Regulation of gene expression, Genetics, Sex Characteristics, Dosage compensation, Tumor, Cultured, Genes, Essential, Genome, Agricultural and Biological Sciences(all), General Neuroscience, Research Support, Non-U.S. Gov't, Biological Sciences, Organ Specificity, Female, General Agricultural and Biological Sciences, Research Article, Human, X Chromosome, Retroelements, QH301-705.5, Neuroscience(all), 1.1 Normal biological development and functioning, Cells, Down-Regulation, Biology, Research Support, General Biochemistry, Genetics and Molecular Biology, Chromosomes, Cell Line, Databases, Genetic, Species Specificity, Underpinning research, Immunology and Microbiology(all), Cell Line, Tumor, Journal Article, Animals, Humans, Comparative Study, Gene, Chromosomes, Human, X, Autosome, General Immunology and Microbiology, Agricultural and Veterinary Sciences, Models, Genetic, Biochemistry, Genetics and Molecular Biology(all), Genome, Human, Mammalian, Human Genome, Chromosomes, Mammalian, Genes, Gene Expression Regulation, Human genome, FANTOM consortium, Developmental Biology
Abstract

X chromosomes are unusual in many regards, not least of which is their nonrandom gene content. The causes of this bias are commonly discussed in the context of sexual antagonism and the avoidance of activity in the male germline. Here, we examine the notion that, at least in some taxa, functionally biased gene content may more profoundly be shaped by limits imposed on gene expression owing to haploid expression of the X chromosome. Notably, if the X, as in primates, is transcribed at rates comparable to the ancestral rate (per promoter) prior to the X chromosome formation, then the X is not a tolerable environment for genes with very high maximal net levels of expression, owing to transcriptional traffic jams. We test this hypothesis using The Encyclopedia of DNA Elements (ENCODE) and data from the Functional Annotation of the Mammalian Genome (FANTOM5) project. As predicted, the maximal expression of human X-linked genes is much lower than that of genes on autosomes: on average, maximal expression is three times lower on the X chromosome than on autosomes. Similarly, autosome-to-X retroposition events are associated with lower maximal expression of retrogenes on the X than seen for X-to-autosome retrogenes on autosomes. Also as expected, X-linked genes have a lesser degree of increase in gene expression than autosomal ones (compared to the human/Chimpanzee common ancestor) if highly expressed, but not if lowly expressed. The traffic jam model also explains the known lower breadth of expression for genes on the X (and the Z of birds), as genes with broad expression are, on average, those with high maximal expression. As then further predicted, highly expressed tissue-specific genes are also rare on the X and broadly expressed genes on the X tend to be lowly expressed, both indicating that the trend is shaped by the maximal expression level not the breadth of expression per se. Importantly, a limit to the maximal expression level explains biased tissue of expression profiles of X-linked genes. Tissues whose tissue-specific genes are very highly expressed (e.g., secretory tissues, tissues abundant in structural proteins) are also tissues in which gene expression is relatively rare on the X chromosome. These trends cannot be fully accounted for in terms of alternative models of biased expression. In conclusion, the notion that it is hard for genes on the Therian X to be highly expressed, owing to transcriptional traffic jams, provides a simple yet robustly supported rationale of many peculiar features of X’s gene content, gene expression, and evolution., Laurence Hurst, Lukasz Huminiecki, and the FANTOM5 consortium propose a new explanation for the peculiar expression properties of genes on the human X chromosome, based on the premise that very high expression levels cannot be achieved on a haploid-expressed chromosome., Author Summary Genes located on the human X chromosome are not a random mix of genes: they tend to be expressed in relatively few tissues or are specific for a particular set of tissues, e.g., brain regions. Prior attempts to explain this skewed gene content have hypothesized that the X chromosome might be peculiar because it has to balance mutations that are advantageous to one sex but deleterious to the other, or because it has to shut down during the process of sperm manufacture in males. Here we suggest and test a third possible explanation: that genes on the X chromosome are limited in their transcription levels and thus tend to be genes that are lowly or specifically expressed. We consider the suggestion that since these genes can only be expressed from one chromosome, as males only have one X, the ability to express a gene at very high rates is limited owing to potential transcriptional traffic jams. As predicted, we find that human X-located genes have maximal expression rates far below that of genes residing on autosomes. When we look at genes that have moved onto or off the X chromosome during recent evolution, we find the maximal expression is higher when not on the X chromosome. We also find that X-located genes that are relatively highly expressed are not able to increase their expression level further. Our model explains both the enrichment for tissue specificity and the paucity of certain tissues with X-located genes. Genes underrepresented on the X are either expressed in many tissues—such genes tend to have high maximal expression—or are from tissues that require a lot of transcription (e.g., fast secreting tissues like the liver). Just as many of the findings cannot be explained by the two earlier models, neither can the traffic jam model explain all the peculiar features of the genes found on the X chromosome. Indeed, we find evidence of a reproduction-related bias in X-located genes, even after allowing for the traffic jam problem.

Published
2015

73. Regulatory T cells (PP-045)

Author

E. Tasaki, Y. Okuno, E. M. Bertram, H. Isaka, S. Delbauve, T. Nakashima, K. A. Newell, J. C. Antvorskov, H. Fan, S. Kawashima, G. Ying, D. Horwitz, T. Thomas, M. Feuerer, Akihiko Yoshimura, C. Elly, K. Wang, T. Kanzaki, K. Buschard, T. P. Arstila, T. Huenig, F. Mair, N. Perdue, J. Sprent, L. Lu, L. Akahira, Y. Yoshida, H. Feng, W. Wang, Howard L. Weiner, Thorsten Buch, T. Laurinolli, D. Lim, F. X. Qin, X. Cao, J. Bártová, Y. m. Cao, I. R. van Driel, S. Hong, C. Tsao, L. M. Kastner, E. M. Ross, J. Wang, T. Honda, S. Park, Y. Chung, S. Schwele, R. Haque, B. Li, T. Yoshikawa, Matthew C. Cook, B. H. Hahn, M. G. Netea, Aleksandar Bulog, I. Iwamoto, J. Liu, P. Fundova, M. Kibata, Y. Lee, C. C. Goodnow, F. Conti, J. S. LeMasurier, Jeffrey A. Bluestone, J. Kie, K. Soejima, N. Erfani, X. R. Zhou, R. J. Steptoe, I. Kim, M. A. Fernandez, C. S. Constantinescu, S. Bauchiero, X. Jin, D. S. Y. Tan, Holly A. Bolton, S. Hu, L. R. Wedderburn, V. Flamand, Z. Liu, K. Sugimura, S. Kunkel, J. M. Rolland, Takatoku Oida, T. Ho, Tobias Bopp, L. Zheng, Y. Li, S. Shen, K. Michishita, M. Shin, R. Germain, Y. Tang, S. Klein-Hessling, Q. h. Wang, X. P. Peng, S. Nakamura, Daniel J. Campbell, Irma Joosten, X. Jiang, M. Braitch, Z. Yao, Masahide Hamaguchi, V. Pancre, H. Lee, Y. Zheng, Y. Cui, W. Müller, R. White, H. Yue, Ai Harashima, J. Perheentupa, M. Tomura, A. T. Endharti, S. Gattenloehner, Kenji Kabashima, M. Goldman, Z. Sarraf, Mihoko Shibuya, T. Sasaki, Y. Kanno, M. Yamamoto, J. Lee, G. Y. Zhou, A. M. Fischer, Y. Kwon, Christophe Benoist, Z. Chen, M. Nakatsugawa, Y. Liu, Y. Park, K. Yamamoto, Dirk H. Busch, C. S. Constantinecsu, T. Hamamoto, A. Carpentier, Y. Zhou, Hans-Dieter Volk, Tomohisa Okamura, J. Tsukada, K. Webster, E. Rabellino, I. Debock, F. Lin, Vladimir Mićović, T. Wakayama, Josef Bodor, H. Bae, G. Metzner, A. Kwan, Ari Waisman, C. Pecli, C. Wu, J. Song, S. Imoto, S. Han, H. Tanizaki, M. Mariotti-Ferrandiz, J. Paik, S. M. Salonen, K. Kawahata, B. Adams, M. H. Nyirenda, C. L. Hardy, K. Isobe, L. M. Lu, J. R. Killebrew, O. Morales, D. P. Funda, A. R. Kendal, A. McNally, R. A. DePinho, Ryuji Iida, N. Sasaki, S. Kim, N. Yang, L. H. Rossi, G. Brestrich, L. Hsu, N. Wada, C. Lu, C. B. Schmidt-Weber, V. Seyfert-Margolis, A. J. van der ven, T. Nakatsura, V. Nikolaev, H. Collins, A. R. Kitching, Carla Jones, B. Yen, Z. J. Jiao, C. Chan, T. Nakagaki, M. Takeuchi, Hirofumi Shoda, G. Lee, G. Wang, T. V. Hogan, M. Plebanski, F. Stenard, F. Liu, A. Suto, T. Otani, K. Tsuji-Takayama, D. E. Furst, Y. Takasaki, Tim Sparwasser, A. Tanaka, M. Asakawa, J. H. Louie, D. Brand, D. W. Dwyer, S. Nakano, A. Okamoto, M. Imamura, L. Chi, C. Zhu, J. Zhu, P. Roubal, S. Dharancy, M. Dohi, E. Kekäläinen, S. I. Alexander, H. Kojima, Dong Han, Q. Wang, N. Delhem, K. Takahashi, D. M. Heery, J. Sun, N. Sakemura, B. Gran, T. Toraya, A. Feng, X. Shen, C. A. Garcia Santana, H. Itoh, S. Zheng, N. MacDonald, U. Behn, A. Facciabene, B. Chiang, W. Kastenmuller, M. W. Leung, Shuji Sumitomo, X. Qu, S. Huang, R. Molinaro, A. Kokešová, M. Bozza, S. Z. Josefowicz, K. Bourcier, D. Bourges, K. Hirose, S. Rahimifar, F. Yamasaki, K. Nistala, E. Serfling, E. Schmitt, Friederike Berberich-Siebelt, Y. Wang, G. Coukos, F. Gross, I. Drexler, L. Yang, T. Gogishvili, S. Kagami, Y. Harada, H. Nakajima, E. Market, Y. Chen, A. Sledzinska, Lin Tian, Amy L. Putnam, F. Cunha, Anthony E.J. Dubois, M. I. Greene, S. Kamei, J. J. Lafaille, D. Kolodin, P. A. Gleeson, Ranjeny Thomas, W. Bolton, Xiao-Sen Li, I. Osawa, C. Miroux, Y. Kang, J. Drbohlav, A. Chaudhry, C. F. Benjamim, C. Kang, A. Ghaderi, G. Zhang, R. P. Singh, M. Hong, S. R. Holdsworth, L. Sanvito, L. Wang, J. j. Wu, T. Kobata, M. Kuo, B. Kim, M. Michels, A. I. Kokaji, Z. Li, W. Shi, J. Yao, X. Xia, W. Chang, S. Choi, R. Nakagawa, Y. y. Pan, M. Vaeth, C. Canetti, F. Lei, P. Hsu, J. Alves-Filho, S. Hori, A. Šalaková, B. L. Wang, J. Wilkinson, P. Zdziarski, M. Fairhurst, Keishi Fujio, X. Zheng, H. Suzuki, R. K. Dinesh, Shimon Sakaguchi, Z. Jiang, S. Hemmers, B Fazekas de St Groth, M. Zelman-Femiak, H. Moncrieffe, L. Han, J. Park, M. Suzuki, S. Eaton, D. Sakurai, T. Inoue, F. Lhommé, S. Nishimoto, Ines Mrakovčić-Šutić, R. Mohamud, Matthias Klein, S. D'Costa, R. E. O'Hehir, N. Morishima, J. Cha, M. Schmueck, M. Uchiyama, K. Imi, H. Hase, E. Boleslowski, A. Liston, C. Park, P. Reinke, C. Shen, H. Wakashin, D. A. Horwitz, Ohkura Naganari, Herman Waldmann, A. Okochi, A. Khoo, I. Kubajewska, J. Seoh, A. Roemhild, Alexander Y. Rudensky, Diane Mathis, J. A. Altin, C. Liu, M. Lohse, T. Shimada, B. Yang, W. Liu, L. Turka, M. Kweon, G. Gasteiger, Hans J. P. M. Koenen, Y. Kim, S. Okuda, Burkhard Becher, and Osami Kanagawa

Subjects
Immunology, Immunology and Allergy, General Medicine
Published
2010

74. Regulatory T cells: roles of T cell receptor for their development and function

Author

Ohkura, Naganari and Sakaguchi, Shimon

Subjects
Foxp3, hemic and immune systems, chemical and pharmacologic phenomena, Regulatory T cells, T cell receptor
Abstract

Naturally arising CD4(+)CD25(+) regulatory T cells (Treg cells), which specifically express the forkhead family transcription factor Foxp3, are essential for the maintenance of immunological self-tolerance and immune homeostasis. Stimulation of the T cell antigen receptor (TCR) via recognizing self-peptide/major histocompatibility complex (MHC) is required for their expression of Foxp3 in the course of their development in the thymus. The TCR repertoires displayed by Treg cells and naïve T cells are apparently distinct, suggesting that Treg cells with high reactivity to self-peptide/MHC ligands are somehow driven to Treg cell lineage in the thymus. Treg cells also require stimulation via TCR to exert suppression in the periphery. At the molecular level, assembly of Foxp3, Foxp3-interacting factors, and chromatin-remodeling factors is in part under the control of TCR signaling, and TCR stimulation alters Foxp3-dependent transcriptional regulation, protein-protein interaction, and Foxp3 recruitment to the specific genomic loci. These findings collectively indicate that the TCR signaling is essential for suppressive function of Treg cells and that TCR has a determinant role for driving developing T cells to the Foxp3(+)CD4(+)CD25(+) Treg cell lineage and differentiation.

Published
2010

75. Lamtor1 Is Critically Required for CD4+ T Cell Proliferation and Regulatory T Cell Suppressive Function

Author

Hosokawa, Takashi, primary, Kimura, Tetsuya, additional, Nada, Shigeyuki, additional, Okuno, Tatsusada, additional, Ito, Daisuke, additional, Kang, Sujin, additional, Nojima, Satoshi, additional, Yamashita, Kazuya, additional, Nakatani, Takeshi, additional, Hayama, Yoshitomo, additional, Kato, Yasuhiro, additional, Kinehara, Yuhei, additional, Nishide, Masayuki, additional, Mikami, Norihisa, additional, Koyama, Syohei, additional, Takamatsu, Hyota, additional, Okuzaki, Daisuke, additional, Ohkura, Naganari, additional, Sakaguchi, Shimon, additional, Okada, Masato, additional, and Kumanogoh, Atsushi, additional

Published
2017
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76. FANTOM5 CAGE profiles of human and mouse samples

Author

Noguchi, Shuhei, primary, Arakawa, Takahiro, additional, Fukuda, Shiro, additional, Furuno, Masaaki, additional, Hasegawa, Akira, additional, Hori, Fumi, additional, Ishikawa-Kato, Sachi, additional, Kaida, Kaoru, additional, Kaiho, Ai, additional, Kanamori-Katayama, Mutsumi, additional, Kawashima, Tsugumi, additional, Kojima, Miki, additional, Kubosaki, Atsutaka, additional, Manabe, Ri-ichiroh, additional, Murata, Mitsuyoshi, additional, Nagao-Sato, Sayaka, additional, Nakazato, Kenichi, additional, Ninomiya, Noriko, additional, Nishiyori-Sueki, Hiromi, additional, Noma, Shohei, additional, Saijyo, Eri, additional, Saka, Akiko, additional, Sakai, Mizuho, additional, Simon, Christophe, additional, Suzuki, Naoko, additional, Tagami, Michihira, additional, Watanabe, Shoko, additional, Yoshida, Shigehiro, additional, Arner, Peter, additional, Axton, Richard A., additional, Babina, Magda, additional, Baillie, J. Kenneth, additional, Barnett, Timothy C., additional, Beckhouse, Anthony G., additional, Blumenthal, Antje, additional, Bodega, Beatrice, additional, Bonetti, Alessandro, additional, Briggs, James, additional, Brombacher, Frank, additional, Carlisle, Ailsa J., additional, Clevers, Hans C., additional, Davis, Carrie A., additional, Detmar, Michael, additional, Dohi, Taeko, additional, Edge, Albert S.B., additional, Edinger, Matthias, additional, Ehrlund, Anna, additional, Ekwall, Karl, additional, Endoh, Mitsuhiro, additional, Enomoto, Hideki, additional, Eslami, Afsaneh, additional, Fagiolini, Michela, additional, Fairbairn, Lynsey, additional, Farach-Carson, Mary C., additional, Faulkner, Geoffrey J., additional, Ferrai, Carmelo, additional, Fisher, Malcolm E., additional, Forrester, Lesley M., additional, Fujita, Rie, additional, Furusawa, Jun-ichi, additional, Geijtenbeek, Teunis B., additional, Gingeras, Thomas, additional, Goldowitz, Daniel, additional, Guhl, Sven, additional, Guler, Reto, additional, Gustincich, Stefano, additional, Ha, Thomas J., additional, Hamaguchi, Masahide, additional, Hara, Mitsuko, additional, Hasegawa, Yuki, additional, Herlyn, Meenhard, additional, Heutink, Peter, additional, Hitchens, Kelly J., additional, Hume, David A., additional, Ikawa, Tomokatsu, additional, Ishizu, Yuri, additional, Kai, Chieko, additional, Kawamoto, Hiroshi, additional, Kawamura, Yuki I., additional, Kempfle, Judith S., additional, Kenna, Tony J., additional, Kere, Juha, additional, Khachigian, Levon M., additional, Kitamura, Toshio, additional, Klein, Sarah, additional, Klinken, S. Peter, additional, Knox, Alan J., additional, Kojima, Soichi, additional, Koseki, Haruhiko, additional, Koyasu, Shigeo, additional, Lee, Weonju, additional, Lennartsson, Andreas, additional, Mackay-sim, Alan, additional, Mejhert, Niklas, additional, Mizuno, Yosuke, additional, Morikawa, Hiromasa, additional, Morimoto, Mitsuru, additional, Moro, Kazuyo, additional, Morris, Kelly J., additional, Motohashi, Hozumi, additional, Mummery, Christine L., additional, Nakachi, Yutaka, additional, Nakahara, Fumio, additional, Nakamura, Toshiyuki, additional, Nakamura, Yukio, additional, Nozaki, Tadasuke, additional, Ogishima, Soichi, additional, Ohkura, Naganari, additional, Ohno, Hiroshi, additional, Ohshima, Mitsuhiro, additional, Okada-Hatakeyama, Mariko, additional, Okazaki, Yasushi, additional, Orlando, Valerio, additional, Ovchinnikov, Dmitry A., additional, Passier, Robert, additional, Patrikakis, Margaret, additional, Pombo, Ana, additional, Pradhan-Bhatt, Swati, additional, Qin, Xian-Yang, additional, Rehli, Michael, additional, Rizzu, Patrizia, additional, Roy, Sugata, additional, Sajantila, Antti, additional, Sakaguchi, Shimon, additional, Sato, Hiroki, additional, Satoh, Hironori, additional, Savvi, Suzana, additional, Saxena, Alka, additional, Schmidl, Christian, additional, Schneider, Claudio, additional, Schulze-Tanzil, Gundula G., additional, Schwegmann, Anita, additional, Sheng, Guojun, additional, Shin, Jay W., additional, Sugiyama, Daisuke, additional, Sugiyama, Takaaki, additional, Summers, Kim M., additional, Takahashi, Naoko, additional, Takai, Jun, additional, Tanaka, Hiroshi, additional, Tatsukawa, Hideki, additional, Tomoiu, Andru, additional, Toyoda, Hiroo, additional, van de Wetering, Marc, additional, van den Berg, Linda M., additional, Verardo, Roberto, additional, Vijayan, Dipti, additional, Wells, Christine A., additional, Winteringham, Louise N., additional, Wolvetang, Ernst, additional, Yamaguchi, Yoko, additional, Yamamoto, Masayuki, additional, Yanagi-Mizuochi, Chiyo, additional, Yoneda, Misako, additional, Yonekura, Yohei, additional, Zhang, Peter G., additional, Zucchelli, Silvia, additional, Abugessaisa, Imad, additional, Arner, Erik, additional, Harshbarger, Jayson, additional, Kondo, Atsushi, additional, Lassmann, Timo, additional, Lizio, Marina, additional, Sahin, Serkan, additional, Sengstag, Thierry, additional, Severin, Jessica, additional, Shimoji, Hisashi, additional, Suzuki, Masanori, additional, Suzuki, Harukazu, additional, Kawai, Jun, additional, Kondo, Naoto, additional, Itoh, Masayoshi, additional, Daub, Carsten O., additional, Kasukawa, Takeya, additional, Kawaji, Hideya, additional, Carninci, Piero, additional, Forrest, Alistair R.R., additional, and Hayashizaki, Yoshihide, additional

Published
2017
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77. A distinct subpopulation of CD25 − T-follicular regulatory cells localizes in the germinal centers

Author

Wing, James Badger, primary, Kitagawa, Yohko, additional, Locci, Michela, additional, Hume, Hannah, additional, Tay, Christopher, additional, Morita, Takayoshi, additional, Kidani, Yujiro, additional, Matsuda, Kyoko, additional, Inoue, Takeshi, additional, Kurosaki, Tomohiro, additional, Crotty, Shane, additional, Coban, Cevayir, additional, Ohkura, Naganari, additional, and Sakaguchi, Shimon, additional

Published
2017
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78. Erratum: Guidance of regulatory T cell development by Satb1-dependent super-enhancer establishment

Author

Kitagawa, Yohko, primary, Ohkura, Naganari, additional, Kidani, Yujiro, additional, Vandenbon, Alexis, additional, Hirota, Keiji, additional, Kawakami, Ryoji, additional, Yasuda, Keiko, additional, Motooka, Daisuke, additional, Nakamura, Shota, additional, Kondo, Motonari, additional, Taniuchi, Ichiro, additional, Kohwi-Shigematsu, Terumi, additional, and Sakaguchi, Shimon, additional

Published
2017
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79. Unique properties of thymic antigen-presenting cells promote epigenetic imprinting of alloantigen-specific regulatory T cells

Author

Garg, Garima, primary, Nikolouli, Eirini, additional, Hardtke-Wolenski, Matthias, additional, Toker, Aras, additional, Ohkura, Naganari, additional, Beckstette, Michael, additional, Miyao, Takahisa, additional, Geffers, Robert, additional, Floess, Stefan, additional, Gerdes, Norbert, additional, Lutgens, Esther, additional, Osterloh, Anke, additional, Hori, Shohei, additional, Sakaguchi, Shimon, additional, Jaeckel, Elmar, additional, and Huehn, Jochen, additional

Published
2017
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80. Guidance of regulatory T cell development by Satb1-dependent super-enhancer establishment

Author

Kitagawa, Yohko, primary, Ohkura, Naganari, additional, Kidani, Yujiro, additional, Vandenbon, Alexis, additional, Hirota, Keiji, additional, Kawakami, Ryoji, additional, Yasuda, Keiko, additional, Motooka, Daisuke, additional, Nakamura, Shota, additional, Kondo, Motonari, additional, Taniuchi, Ichiro, additional, Kohwi-Shigematsu, Terumi, additional, and Sakaguchi, Shimon, additional

Published
2016
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81. Regulatory T cells expressing abundant CTLA‐4 on the cell surface with a proliferative gene profile are key features of human head and neck cancer.

Author

Matoba, Takuma, Imai, Masaki, Ohkura, Naganari, Kawakita, Daisuke, Ijichi, Kei, Toyama, Tatsuya, Morita, Akimichi, Murakami, Shingo, Sakaguchi, Shimon, and Yamazaki, Sayuri

Abstract

FOXP3+ regulatory T (Treg) cells suppress anti‐tumor immunity. The suppression of Treg cells is regulated by cytotoxic T‐lymphocyte‐associated antigen‐4 (CTLA‐4), whose expression on the cell surface is tightly regulated. Here we found that Treg cells expressing abundant CTLA‐4 on the cell surface (surface‐CTLA‐4+ Treg) were expanded in human head and neck cancer tissues. RNA sequencing of surface‐CTLA‐4+ and surface‐CTLA‐4− Treg cells infiltrating human head and neck cancer tissues revealed that surface‐CTLA‐4+ Treg cells have a previously undescribed gene expression profile correlating to cell cycle, cell proliferation, and DNA replication. Moreover, surface‐CTLA‐4+ Treg cells were PD‐1+, actively proliferated and associated with CD45RA− FOXP3high Treg cells with strong suppressive function. Thus, surface‐CTLA‐4+ Treg cells with a proliferative gene expression signature and phenotype are key features of head and neck cancer. Targeting surface‐CTLA‐4+ Treg cells might be new strategies to evoke effective immune responses to head and neck cancer. What's new? Regulatory T (Treg) cells have been shown to suppress anti‐tumor immunity. CTLA‐4 is key in controlling Treg function, but its importance in head and neck cancer remains unclear. Here, the authors found that Treg cells with abundant CTLA‐4 on the cell surface (surface‐CTLA‐4+ Treg) were expanded in human head and neck cancer. This is surprising because most CTLA‐4 is generally expressed intracellularly. Surface‐CTLA‐4+ Treg cells in human head and neck cancer highly expressed previously‐undescribed genes correlated to cell cycle, cell proliferation, and DNA replication. Targeting surface‐CTLA‐4+ Treg cells might lead to new strategies for eliciting anti‐tumor immunity in human cancer. [ABSTRACT FROM AUTHOR]

Published
2019
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82. Innate Myeloid Cell Subset-Specific Gene Expression Patterns in the Human Colon are Altered in Crohn's Disease Patients.

Author

Sekido, Yuki, Yasumizu, Yoshiaki, Nishimura, Junichi, Kayama, Hisako, Matsuno, Hiroshi, Ogino, Takayuki, Miyoshi, Norikatsu, Takahashi, Hidekazu, Haraguchi, Naotsugu, Hata, Taishi, Matsuda, Chu, Doki, Yuichiro, Mori, Masaki, Takeda, Kiyoshi, Ohkura, Naganari, Sakaguchi, Shimon, and Mizushima, Tsunekazu

Subjects
CROHN'S disease, GENE expression, GENE expression profiling, INFLAMMATORY bowel diseases, DENDRITIC cells
Abstract

Background/Aims: There is a heterogeneous subset innate myeloid cells, such as macrophages and dendritic cells, in the human intestinal lamina propria. Several studies have demonstrated that these cells contribute to the maintenance of gut homeostasis through the induction of inflammatory responses and tolerance via cell type-specific mechanisms; whereas, disrupted innate immune responses are implicated in the pathogenesis of Crohn's disease (CD). However, the detailed mechanisms by which each innate myeloid subset regulates gut homeostasis and inflammation largely remain unknown. We aimed to clarify the comprehensive gene expression profiles of innate myeloid cell -subsets in the lamina propria from normal human colons (NC) and the inflamed colon sites from patients with Crohn's disease (CDi). Methods: We performed RNA-sequencing analysis and precise bioinformatics analysis on 3 innate myeloid cell subsets, CD14–CD11c–, CD14–CD11c+, and CD14+CD11c+CD163low cells from NC and CDi. Results: Transcriptional analysis of the 3 subsets from the NC showed distinct gene expression patterns and gene ontology (GO) enrichment analysis revealed the associated innate myeloid subset-specific biological process (BP) terms. In addition, changes in gene expression patterns were observed in innate myeloid subsets from CDi. Furthermore, the core GO-BP terms for the genes upregulated in the innate myeloid cells from CDi were distinct from those found in NC. Conclusion: Our data identified the innate myeloid cell subset-specific transcriptomes and the associated enriched GO-BP terms in the NC and found these patterns were altered in CDi. [ABSTRACT FROM AUTHOR]

Published
2019
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83. VIRTUS: a pipeline for comprehensive virus analysis from conventional RNA-seq data.

Author

Yasumizu, Yoshiaki, Hara, Atsushi, Sakaguchi, Shimon, and Ohkura, Naganari

Subjects
HERPESVIRUSES, VIRUS diseases, RNA sequencing, RNA viruses, COVID-19, VIRUSES
Abstract

Summary The possibility that RNA transcripts from clinical samples contain plenty of virus RNAs has not been pursued actively so far. We here developed a new tool for analyzing virus-transcribed mRNAs, not virus copy numbers, in the data of bulk and single-cell RNA-sequencing of human cells. Our pipeline, named VIRTUS (VIRal Transcript Usage Sensor), was able to detect 762 viruses including herpesviruses, retroviruses and even SARS-CoV-2 (COVID-19), and quantify their transcripts in the sequence data. This tool thus enabled simultaneously detecting infected cells, the composition of multiple viruses within the cell, and the endogenous host-gene expression profile of the cell. This bioinformatics method would be instrumental in addressing the possible effects of covertly infecting viruses on certain diseases and developing new treatments to target such viruses. Availability and implementation : VIRTUS is implemented using Common Workflow Language and Docker under a CC-NC license. VIRTUS is freely available at https://github.com/yyoshiaki/VIRTUS. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Published
2021
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84. Human Foxp3-negative follicular regulatory T cells control IgE responses

Author

Canete, Pablo, Sweet, Rebecca, Papa, Ilenia, Gonzalez-Figueroa, Paula, Ohkura, Naganari, Cuenca, Marta, Cayetano, Alyssa, Ohms, Stephen J, Barry, E, Grimbaldeston, Michele, Sakaguchi, Shimon, Prof, Cook, Matthew, Garcia De Vinuesa, Maria Carola, Canete, Pablo, Sweet, Rebecca, Papa, Ilenia, Gonzalez-Figueroa, Paula, Ohkura, Naganari, Cuenca, Marta, Cayetano, Alyssa, Ohms, Stephen J, Barry, E, Grimbaldeston, Michele, Sakaguchi, Shimon, Prof, Cook, Matthew, and Garcia De Vinuesa, Maria Carola

Abstract

Antibody responses to most infectious and food protein antigens depend on help to B cells from specialised T follicular helper (Tfh) cells. A subset of Foxp3+ regulatory T cells (Tregs) has been described in mice, with a prominent role in repressing germinal center reactions that are critical for memory B cell formation and long-lived antibody responses. These specialised Tregs co-opt the Bcl-6-dependent Tfh differentiation pathway in order to access the B cell-rich follicles and have therefore been designated as T follicular regulatory (Tfr) cells.

Published
2016

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

Author

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, FANTOM Consortium, 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, and FANTOM Consortium

Abstract

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.

Published
2014

88. A promoter-level mammalian expression atlas

Author

Forest, 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, Young, Robert S., Francescatto, Margherita, Altschuler, Intikhab Alam, Albanese, Davide, Altschule, Gabriel M., Arakawa, Takahiro, Archer, John A C, Arner, Peter, Babina, Magda, Rennie, 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., 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 P., 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, De Morais, David A 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, Suzuki, Naoko, Swoboda, Rolf K., 'T Hoen, Peter A C, Tagami, Michihira, Tagami, Naoko Takahashi, 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, Susan 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, Lenhard Vladimir B, Taylor, Martin S., Makeev, Vsevolod J., Sandelin, Albin Gustav, Hume, David A., Carninci, Piero, Hayashizaki, Yoshihide, Forest, 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, Young, Robert S., Francescatto, Margherita, Altschuler, Intikhab Alam, Albanese, Davide, Altschule, Gabriel M., Arakawa, Takahiro, Archer, John A C, Arner, Peter, Babina, Magda, Rennie, 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., 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 P., 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, De Morais, David A 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, Suzuki, Naoko, Swoboda, Rolf K., 'T Hoen, Peter A C, Tagami, Michihira, Tagami, Naoko Takahashi, 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, Susan 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, Lenhard Vladimir B, Taylor, Martin S., Makeev, Vsevolod J., Sandelin, Albin Gustav, Hume, David A., Carninci, Piero, and Hayashizaki, Yoshihide

Abstract

Regulated transcription controls the diversity, developmental pathways and spatial organization of the hundreds of cell types that make up a mammal. Using single-molecule cDNA sequencing, we mapped transcription start sites (TSSs) and their usage in human and mouse primary cells, cell lines and tissues to produce a comprehensive overview of mammalian gene expression across the human body. We find that few genes are truly â ̃ housekeepingâ ™, whereas many mammalian promoters are composite entities composed of several closely separated TSSs, with independent cell-type-specific expression profiles. TSSs specific to different cell types evolve at different rates, whereas promoters of broadly expressed genes are the most conserved. Promoter-based expression analysis reveals key transcription factors defining cell states and links them to binding-site motifs. The functions of identified novel transcripts can be predicted by coexpression and sample ontology enrichment analyses. The functional annotation of the mammalian genome 5 (FANTOM5) project provides comprehensive expression profiles and functional annotation of mammalian cell-type-specific transcriptomes with wide applications in biomedical research.

Published
2014

96. HTLV-1 bZIP Factor Induces T-Cell Lymphoma and Systemic Inflammation In Vivo

Author

Satou, Yorifumi, primary, Yasunaga, Jun-ichirou, additional, Zhao, Tiejun, additional, Yoshida, Mika, additional, Miyazato, Paola, additional, Takai, Ken, additional, Shimizu, Kei, additional, Ohshima, Koichi, additional, Green, Patrick L., additional, Ohkura, Naganari, additional, Yamaguchi, Tomoyuki, additional, Ono, Masahiro, additional, Sakaguchi, Shimon, additional, and Matsuoka, Masao, additional

Published
2011
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99. Epigenetic control of thymic Treg-cell development.

Author

Kitagawa, Yohko, Ohkura, Naganari, and Sakaguchi, Shimon

Abstract

Thymus-derived Treg cells, which express the transcription factor Foxp3, form a functionally stable cell lineage indispensable for the maintenance of immunological self-tolerance and homeostasis. Foxp3 is critically required for Treg-cell function, in particular for their suppressive function. Recent studies have implicated the contribution of Treg-cell-specific epigenetic modifications as a means to ensure the stable expression of Foxp3 and other molecules associated with Treg-cell function. Unexpectedly, epigenetic modifications introduced in the course of thymic Treg-cell development were found to be independent of Foxp3 expression. These findings require reconsideration of the current model of Treg-cell development based on Foxp3 induction. With reference to other examples of lineage specification, we discuss possible models for thymic Treg-cell development. [ABSTRACT FROM AUTHOR]

Published
2015
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