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1. Discovery of widespread transcription initiation at microsatellites predictable by sequence-based deep neural network

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Grapotte M., Saraswat M., Bessiere C., Menichelli C., Ramilowski J. A., Severin J., Hayashizaki Y., Itoh M., Tagami M., Murata M., Kojima-Ishiyama M., Noma S., Noguchi S., Kasukawa T., Hasegawa A., Suzuki H., Nishiyori-Sueki H., Frith M. C., Abugessaisa I., Aitken S., Aken B. L., Alam I., Alam T., Alasiri R., Alhendi A. M. N., Alinejad-Rokny H., Alvarez M. J., Andersson R., Arakawa T., Araki M., Arbel T., Archer J., Archibald A. L., Arner E., Arner P., Asai K., Ashoor H., Astrom G., Babina M., Baillie J. K., Bajic V. B., Bajpai A., Baker S., Baldarelli R. M., Balic A., Bansal M., Batagov A. O., Batzoglou S., Beckhouse A. G., Beltrami A. P., Beltrami C. A., Bertin N., Bhattacharya S., Bickel P. J., Blake J. A., Blanchette M., Bodega B., Bonetti A., Bono H., Bornholdt J., Bttcher M., Bougouffa S., Boyd M., Breda J., Brombacher F., Brown J. B., Bult C. J., Burroughs A. M., Burt D. W., Busch A., Caglio G., Califano A., Cameron C. J., Cannistraci C. V., Carbone A., Carlisle A. J., Carninci P., Carter K. W., Cesselli D., Chang J. -C., Chen J. C., Chen Y., Chierici M., Christodoulou J., Ciani Y., Clark E. L., Coskun M., Dalby M., Dalla E., Daub C. O., Davis C. A., de Hoon M. J. L., de Rie D., Denisenko E., Deplancke B., Detmar M., Deviatiiarov R., Di Bernardo D., Diehl A. D., Dieterich L. C., Dimont E., Djebali S., Dohi T., Dostie J., Drablos F., Edge A. S. B., Edinger M., Ehrlund A., Ekwall K., Elofsson A., Endoh M., Enomoto H., Enomoto S., Faghihi M., Fagiolini M., Farach-Carson M. C., Faulkner G. J., Favorov A., Fernandes A. M., Ferrai C., Forrest A. R. R., Forrester L. M., Forsberg M., Fort A., Francescatto M., Freeman T. C., Frith M., Fukuda S., Funayama M., Furlanello C., Furuno M., Furusawa C., Gao H., Gazova I., Gebhard C., Geier F., Geijtenbeek T. B. H., Ghosh S., Ghosheh Y., Gingeras T. R., Gojobori T., Goldberg T., Goldowitz D., Gough J., Greco D., Gruber A. J., Guhl S., Guigo R., Guler R., Gusev O., Gustincich S., Ha T. J., Haberle V., Hale P., Hallstrom B. M., Hamada M., Handoko L., Hara M., Harbers M., Harrow J., Harshbarger J., Hase T., Hashimoto K., Hatano T., Hattori N., Hayashi R., Herlyn M., Hettne K., Heutink P., Hide W., Hitchens K. J., Sui S. H., 't Hoen P. A. C., Hon C. C., Hori F., Horie M., Horimoto K., Horton P., Hou R., Huang E., Huang Y., Hugues R., Hume D., Ienasescu H., Iida K., Ikawa T., Ikemura T., Ikeo K., Inoue N., Ishizu Y., Ito Y., Ivshina A. V., Jankovic B. R., Jenjaroenpun P., Johnson R., Jorgensen M., Jorjani H., Joshi A., Jurman G., Kaczkowski B., Kai C., Kaida K., Kajiyama K., Kaliyaperumal R., Kaminuma E., Kanaya T., Kaneda H., Kapranov P., Kasianov A. S., Katayama T., Kato S., Kawaguchi S., Kawai J., Kawaji H., Kawamoto H., Kawamura Y. I., Kawasaki S., Kawashima T., Kempfle J. S., Kenna T. J., Kere J., Khachigian L., Kiryu H., Kishima M., Kitajima H., Kitamura T., Kitano H., Klaric E., Klepper K., Klinken S. P., Kloppmann E., Knox A. J., Kodama Y., Kogo Y., Kojima M., Kojima S., Komatsu N., Komiyama H., Kono T., Koseki H., Koyasu S., Kratz A., Kukalev A., Kulakovskiy I., Kundaje A., Kunikata H., Kuo R., Kuo T., Kuraku S., Kuznetsov V. A., Kwon T. J., Larouche M., Lassmann T., Law A., Le-Cao K. -A., Lecellier C. -H., Lee W., Lenhard B., Lennartsson A., Li K., Li R., Lilje B., Lipovich L., Lizio M., Lopez G., Magi S., Mak G. K., Makeev V., Manabe R., Mandai M., Mar J., Maruyama K., Maruyama T., Mason E., Mathelier A., Matsuda H., Medvedeva Y. A., Meehan T. F., Mejhert N., Meynert A., Mikami N., Minoda A., Miura H., Miyagi Y., Miyawaki A., Mizuno Y., Morikawa H., Morimoto M., Morioka M., Morishita S., Moro K., Motakis E., Motohashi H., Mukarram A. K., Mummery C. L., Mungall C. J., Murakawa Y., Muramatsu M., Nagasaka K., Nagase T., Nakachi Y., Nakahara F., Nakai K., Nakamura K., Nakamura Y., Nakazawa T., Nason G. P., Nepal C., Nguyen Q. H., Nielsen L. K., Nishida K., Nishiguchi K. M., Nishiyori H., Nitta K., Notredame C., Ogishima S., Ohkura N., Ohno H., Ohshima M., Ohtsu T., Okada Y., Okada-Hatakeyama M., Okazaki Y., Oksvold P., Orlando V., Ow G. S., Ozturk M., Pachkov M., Paparountas T., Parihar S. P., Park S. -J., Pascarella G., Passier R., Persson H., Philippens I. H., Piazza S., Plessy C., Pombo A., Ponten F., Poulain S., Poulsen T. M., Pradhan S., Prezioso C., Pridans C., Qin X. -Y., Quackenbush J., Rackham O., Ramilowski J., Ravasi T., Rehli M., Rennie S., Rito T., Rizzu P., Robert C., Roos M., Rost B., Roudnicky F., Roy R., Rye M. B., Sachenkova O., Saetrom P., Sai H., Saiki S., Saito M., Saito A., Sakaguchi S., Sakai M., Sakaue S., Sakaue-Sawano A., Sandelin A., Sano H., Sasamoto Y., Sato H., Saxena A., Saya H., Schafferhans A., Schmeier S., Schmidl C., Schmocker D., Schneider C., Schueler M., Schultes E. A., Schulze-Tanzil G., Semple C. A., Seno S., Seo W., Sese J., Sheng G., Shi J., Shimoni Y., Shin J. W., SimonSanchez J., Sivertsson A., Sjostedt E., Soderhall C., Laurent G. S., Stoiber M. H., Sugiyama D., Summers K. M., Suzuki A. M., Suzuki K., Suzuki M., Suzuki N., Suzuki T., Swanson D. J., Swoboda R. K., Taguchi A., Takahashi H., Takahashi M., Takamochi K., Takeda S., Takenaka Y., Tam K. T., Tanaka H., Tanaka R., Tanaka Y., Tang D., Taniuchi I., Tanzer A., Tarui H., Taylor M. S., Terada A., Terao Y., Testa A. C., Thomas M., Thongjuea S., Tomii K., Triglia E. T., Toyoda H., Tsang H. G., Tsujikawa M., Uhlen M., Valen E., van de Wetering M., van Nimwegen E., Velmeshev D., Verardo R., Vitezic M., Vitting-Seerup K., von Feilitzen K., Voolstra C. R., Vorontsov I. E., Wahlestedt C., Wasserman W. W., Watanabe K., Watanabe S., Wells C. A., Winteringham L. N., Wolvetang E., Yabukami H., Yagi K., Yamada T., Yamaguchi Y., Yamamoto M., Yamamoto Y., Yamanaka Y., Yano K., Yasuzawa K., Yatsuka Y., Yo M., Yokokura S., Yoneda M., Yoshida E., Yoshida Y., Yoshihara M., Young R., Young R. S., Yu N. Y., Yumoto N., Zabierowski S. E., Zhang P. G., Zucchelli S., Zwahlen M., Chatelain C., Brehelin L., Grapotte, M., Saraswat, M., Bessiere, C., Menichelli, C., Ramilowski, J. A., Severin, J., Hayashizaki, Y., Itoh, M., Tagami, M., Murata, M., Kojima-Ishiyama, M., Noma, S., Noguchi, S., Kasukawa, T., Hasegawa, A., Suzuki, H., Nishiyori-Sueki, H., Frith, M. C., Abugessaisa, I., Aitken, S., Aken, B. L., Alam, I., Alam, T., Alasiri, R., Alhendi, A. M. N., Alinejad-Rokny, H., Alvarez, M. J., Andersson, R., Arakawa, T., Araki, M., Arbel, T., Archer, J., Archibald, A. L., Arner, E., Arner, P., Asai, K., Ashoor, H., Astrom, G., Babina, M., Baillie, J. K., Bajic, V. B., Bajpai, A., Baker, S., Baldarelli, R. M., Balic, A., Bansal, M., Batagov, A. O., Batzoglou, S., Beckhouse, A. G., Beltrami, A. P., Beltrami, C. A., Bertin, N., Bhattacharya, S., Bickel, P. J., Blake, J. A., Blanchette, M., Bodega, B., Bonetti, A., Bono, H., Bornholdt, J., Bttcher, M., Bougouffa, S., Boyd, M., Breda, J., Brombacher, F., Brown, J. B., Bult, C. J., Burroughs, A. M., Burt, D. W., Busch, A., Caglio, G., Califano, A., Cameron, C. J., Cannistraci, C. V., Carbone, A., Carlisle, A. J., Carninci, P., Carter, K. W., Cesselli, D., Chang, J. -C., Chen, J. C., Chen, Y., Chierici, M., Christodoulou, J., Ciani, Y., Clark, E. L., Coskun, M., Dalby, M., Dalla, E., Daub, C. O., Davis, C. A., de Hoon, M. J. L., de Rie, D., Denisenko, E., Deplancke, B., Detmar, M., Deviatiiarov, R., Di Bernardo, D., Diehl, A. D., Dieterich, L. C., Dimont, E., Djebali, S., Dohi, T., Dostie, J., Drablos, F., Edge, A. S. B., Edinger, M., Ehrlund, A., Ekwall, K., Elofsson, A., Endoh, M., Enomoto, H., Enomoto, S., Faghihi, M., Fagiolini, M., Farach-Carson, M. C., Faulkner, G. J., Favorov, A., Fernandes, A. M., Ferrai, C., Forrest, A. R. R., Forrester, L. M., Forsberg, M., Fort, A., Francescatto, M., Freeman, T. C., Frith, M., Fukuda, S., Funayama, M., Furlanello, C., Furuno, M., Furusawa, C., Gao, H., Gazova, I., Gebhard, C., Geier, F., Geijtenbeek, T. B. H., Ghosh, S., Ghosheh, Y., Gingeras, T. R., Gojobori, T., Goldberg, T., Goldowitz, D., Gough, J., Greco, D., Gruber, A. J., Guhl, S., Guigo, R., Guler, R., Gusev, O., Gustincich, S., Ha, T. J., Haberle, V., Hale, P., Hallstrom, B. M., Hamada, M., Handoko, L., Hara, M., Harbers, M., Harrow, J., Harshbarger, J., Hase, T., Hashimoto, K., Hatano, T., Hattori, N., Hayashi, R., Herlyn, M., Hettne, K., Heutink, P., Hide, W., Hitchens, K. J., Sui, S. H., 't Hoen, P. A. C., Hon, C. C., Hori, F., Horie, M., Horimoto, K., Horton, P., Hou, R., Huang, E., Huang, Y., Hugues, R., Hume, D., Ienasescu, H., Iida, K., Ikawa, T., Ikemura, T., Ikeo, K., Inoue, N., Ishizu, Y., Ito, Y., Ivshina, A. V., Jankovic, B. R., Jenjaroenpun, P., Johnson, R., Jorgensen, M., Jorjani, H., Joshi, A., Jurman, G., Kaczkowski, B., Kai, C., Kaida, K., Kajiyama, K., Kaliyaperumal, R., Kaminuma, E., Kanaya, T., Kaneda, H., Kapranov, P., Kasianov, A. S., Katayama, T., Kato, S., Kawaguchi, S., Kawai, J., Kawaji, H., Kawamoto, H., Kawamura, Y. I., Kawasaki, S., Kawashima, T., Kempfle, J. S., Kenna, T. J., Kere, J., Khachigian, L., Kiryu, H., Kishima, M., Kitajima, H., Kitamura, T., Kitano, H., Klaric, E., Klepper, K., Klinken, S. P., Kloppmann, E., Knox, A. J., Kodama, Y., Kogo, Y., Kojima, M., Kojima, S., Komatsu, N., Komiyama, H., Kono, T., Koseki, H., Koyasu, S., Kratz, A., Kukalev, A., Kulakovskiy, I., Kundaje, A., Kunikata, H., Kuo, R., Kuo, T., Kuraku, S., Kuznetsov, V. A., Kwon, T. J., Larouche, M., Lassmann, T., Law, A., Le-Cao, K. -A., Lecellier, C. -H., Lee, W., Lenhard, B., Lennartsson, A., Li, K., Li, R., Lilje, B., Lipovich, L., Lizio, M., Lopez, G., Magi, S., Mak, G. K., Makeev, V., Manabe, R., Mandai, M., Mar, J., Maruyama, K., Maruyama, T., Mason, E., Mathelier, A., Matsuda, H., Medvedeva, Y. A., Meehan, T. F., Mejhert, N., Meynert, A., Mikami, N., Minoda, A., Miura, H., Miyagi, Y., Miyawaki, A., Mizuno, Y., Morikawa, H., Morimoto, M., Morioka, M., Morishita, S., Moro, K., Motakis, E., Motohashi, H., Mukarram, A. K., Mummery, C. L., Mungall, C. J., Murakawa, Y., Muramatsu, M., Nagasaka, K., Nagase, T., Nakachi, Y., Nakahara, F., Nakai, K., Nakamura, K., Nakamura, Y., Nakazawa, T., Nason, G. P., Nepal, C., Nguyen, Q. H., Nielsen, L. K., Nishida, K., Nishiguchi, K. M., Nishiyori, H., Nitta, K., Notredame, C., Ogishima, S., Ohkura, N., Ohno, H., Ohshima, M., Ohtsu, T., Okada, Y., Okada-Hatakeyama, M., Okazaki, Y., Oksvold, P., Orlando, V., Ow, G. S., Ozturk, M., Pachkov, M., Paparountas, T., Parihar, S. P., Park, S. -J., Pascarella, G., Passier, R., Persson, H., Philippens, I. H., Piazza, S., Plessy, C., Pombo, A., Ponten, F., Poulain, S., Poulsen, T. M., Pradhan, S., Prezioso, C., Pridans, C., Qin, X. -Y., Quackenbush, J., Rackham, O., Ramilowski, J., Ravasi, T., Rehli, M., Rennie, S., Rito, T., Rizzu, P., Robert, C., Roos, M., Rost, B., Roudnicky, F., Roy, R., Rye, M. B., Sachenkova, O., Saetrom, P., Sai, H., Saiki, S., Saito, M., Saito, A., Sakaguchi, S., Sakai, M., Sakaue, S., Sakaue-Sawano, A., Sandelin, A., Sano, H., Sasamoto, Y., Sato, H., Saxena, A., Saya, H., Schafferhans, A., Schmeier, S., Schmidl, C., Schmocker, D., Schneider, C., Schueler, M., Schultes, E. A., Schulze-Tanzil, G., Semple, C. A., Seno, S., Seo, W., Sese, J., Sheng, G., Shi, J., Shimoni, Y., Shin, J. W., Simonsanchez, J., Sivertsson, A., Sjostedt, E., Soderhall, C., Laurent, G. S., Stoiber, M. H., Sugiyama, D., Summers, K. M., Suzuki, A. M., Suzuki, K., Suzuki, M., Suzuki, N., Suzuki, T., Swanson, D. J., Swoboda, R. K., Taguchi, A., Takahashi, H., Takahashi, M., Takamochi, K., Takeda, S., Takenaka, Y., Tam, K. T., Tanaka, H., Tanaka, R., Tanaka, Y., Tang, D., Taniuchi, I., Tanzer, A., Tarui, H., Taylor, M. S., Terada, A., Terao, Y., Testa, A. C., Thomas, M., Thongjuea, S., Tomii, K., Triglia, E. T., Toyoda, H., Tsang, H. G., Tsujikawa, M., Uhlen, M., Valen, E., van de Wetering, M., van Nimwegen, E., Velmeshev, D., Verardo, R., Vitezic, M., Vitting-Seerup, K., von Feilitzen, K., Voolstra, C. R., Vorontsov, I. E., Wahlestedt, C., Wasserman, W. W., Watanabe, K., Watanabe, S., Wells, C. A., Winteringham, L. N., Wolvetang, E., Yabukami, H., Yagi, K., Yamada, T., Yamaguchi, Y., Yamamoto, M., Yamamoto, Y., Yamanaka, Y., Yano, K., Yasuzawa, K., Yatsuka, Y., Yo, M., Yokokura, S., Yoneda, M., Yoshida, E., Yoshida, Y., Yoshihara, M., Young, R., Young, R. S., Yu, N. Y., Yumoto, N., Zabierowski, S. E., Zhang, P. G., Zucchelli, S., Zwahlen, M., Chatelain, C., Brehelin, L., Institute of Biotechnology, Biosciences, Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Computationnelle (IBC), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Méthodes et Algorithmes pour la Bioinformatique (MAB), Laboratoire d'Informatique de Robotique et de Microélectronique de Montpellier (LIRMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), National Institute of Advanced Industrial Science and Technology (AIST), SANOFI Recherche, University of British Columbia (UBC), Experimental Immunology, Infectious diseases, AII - Infectious diseases, Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), and Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Montpellier (UM)

Subjects
0301 basic medicine, General Physics and Astronomy, Genome, Mice, 0302 clinical medicine, Transcription (biology), Promoter Regions, Genetic, Transcription Initiation, Genetic, 0303 health sciences, Multidisciplinary, 1184 Genetics, developmental biology, physiology, High-Throughput Nucleotide Sequencing, Neurodegenerative Diseases, 222 Other engineering and technologies, Genomics, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], humanities, Enhancer Elements, Genetic, Microsatellite Repeat, Transcription Initiation Site, Sequence motif, Transcription Initiation, Human, Enhancer Elements, Neural Networks, Science, 610 Medicine & health, Computational biology, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Promoter Regions, 03 medical and health sciences, Computer, Deep Learning, Tandem repeat, Genetic, Clinical Research, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Machine learning, Genetics, Animals, Humans, Polymorphism, Enhancer, Transcriptomics, Gene, A549 Cell, 030304 developmental biology, Polymorphism, Genetic, Neurodegenerative Disease, Base Sequence, Animal, Genome, Human, Human Genome, Computational Biology, Promoter, General Chemistry, 113 Computer and information sciences, Cap analysis gene expression, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Cardiovascular and Metabolic Diseases, A549 Cells, Minion, Generic health relevance, 3111 Biomedicine, Neural Networks, Computer, 610 Medizin und Gesundheit, 030217 neurology & neurosurgery, FANTOM consortium, Microsatellite Repeats
Abstract

Using the Cap Analysis of Gene Expression (CAGE) technology, the FANTOM5 consortium provided one of the most comprehensive maps of transcription start sites (TSSs) in several species. Strikingly, ~72% of them could not be assigned to a specific gene and initiate at unconventional regions, outside promoters or enhancers. Here, we probe these unassigned TSSs and show that, in all species studied, a significant fraction of CAGE peaks initiate at microsatellites, also called short tandem repeats (STRs). To confirm this transcription, we develop Cap Trap RNA-seq, a technology which combines cap trapping and long read MinION sequencing. We train sequence-based deep learning models able to predict CAGE signal at STRs with high accuracy. These models unveil the importance of STR surrounding sequences not only to distinguish STR classes, but also to predict the level of transcription initiation. Importantly, genetic variants linked to human diseases are preferentially found at STRs with high transcription initiation level, supporting the biological and clinical relevance of transcription initiation at STRs. Together, our results extend the repertoire of non-coding transcription associated with DNA tandem repeats and complexify STR polymorphism., Nature Communications, 12 (1), ISSN:2041-1723

Published
2020
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7. Data Descriptor: FANTOM5 CAGE profiles of human and mouse samples

Author

Noguchi, S, Arakawa, T, Fukuda, S, Furuno, M, Hasegawa, A, Hori, F, Ishikawa-Kato, S, Kaida, K, Kaiho, A, Kanamori-Katayama, M, Kawashima, T, Kojima, M, Kubosaki, A, Manabe, R-I, Murata, M, Nagao-Sato, S, Nakazato, K, Ninomiya, N, Nishiyori-Sueki, H, Noma, S, Saijyo, E, Saka, A, Sakai, M, Simon, C, Suzuki, N, Tagami, M, Watanabe, S, Yoshida, S, Arner, P, Axton, RA, Babina, M, Baillie, JK, Barnett, TC, Beckhouse, AG, Blumenthal, A, Bodega, B, Bonetti, A, Briggs, J, Brombacher, F, Carlisle, AJ, Clevers, HC, Davis, CA, Detmar, M, Dohi, T, Edge, ASB, Edinger, M, Ehrlund, A, Ekwall, K, Endoh, M, Enomoto, H, Eslami, A, Fagiolini, M, Fairbairn, L, Farach-Carson, MC, Faulkner, GJ, Ferrai, C, Fisher, ME, Forrester, LM, Fujita, R, Furusawa, J-I, Geijtenbeek, TB, Gingeras, T, Goldowitz, D, Guhl, S, Guler, R, Gustincich, S, Ha, TJ, Hamaguchi, M, Hara, M, Hasegawa, Y, Herlyn, M, Heutink, P, Hitchens, KJ, Hume, DA, Ikawa, T, Ishizu, Y, Kai, C, Kawamoto, H, Kawamura, YI, Kempfle, JS, Kenna, TJ, Kere, J, Khachigian, LM, Kitamura, T, Klein, S, Klinken, SP, Knox, AJ, Kojima, S, Koseki, H, Koyasu, S, Lee, W, Lennartsson, A, Mackay-sim, A, Mejhert, N, Mizuno, Y, Morikawa, H, Morimoto, M, Moro, K, Morris, KJ, Motohashi, H, Mummery, CL, Nakachi, Y, Nakahara, F, Nakamura, T, Nakamura, Y, Nozaki, T, Ogishima, S, Ohkura, N, Ohno, H, Ohshima, M, Okada-Hatakeyama, M, Okazaki, Y, Orlando, V, Ovchinnikov, DA, Passier, R, Patrikakis, M, Pombo, A, Pradhan-Bhatt, S, Qin, X-Y, Rehli, M, Rizzu, P, Roy, S, Sajantila, A, Sakaguchi, S, Sato, H, Satoh, H, Savvi, S, Saxena, A, Schmidl, C, Schneider, C, Schulze-Tanzil, GG, Schwegmann, A, Sheng, G, Shin, JW, Sugiyama, D, Sugiyama, T, Summers, KM, Takahashi, N, Takai, J, Tanaka, H, Tatsukawa, H, Tomoiu, A, Toyoda, H, van de Wetering, M, van den Berg, LM, Verardo, R, Vijayan, D, Wells, CA, Winteringham, LN, Wolvetang, E, Yamaguchi, Y, Yamamoto, M, Yanagi-Mizuochi, C, Yoneda, M, Yonekura, Y, Zhang, PG, Zucchelli, S, Abugessaisa, I, Arner, E, Harshbarger, J, Kondo, A, Lassmann, T, Lizio, M, Sahin, S, Sengstag, T, Severin, J, Shimoji, H, Suzuki, M, Suzuki, H, Kawai, J, Kondo, N, Itoh, M, Daub, CO, Kasukawa, T, Kawaji, H, Carninci, P, Forrest, ARR, Hayashizaki, Y, Noguchi, S, Arakawa, T, Fukuda, S, Furuno, M, Hasegawa, A, Hori, F, Ishikawa-Kato, S, Kaida, K, Kaiho, A, Kanamori-Katayama, M, Kawashima, T, Kojima, M, Kubosaki, A, Manabe, R-I, Murata, M, Nagao-Sato, S, Nakazato, K, Ninomiya, N, Nishiyori-Sueki, H, Noma, S, Saijyo, E, Saka, A, Sakai, M, Simon, C, Suzuki, N, Tagami, M, Watanabe, S, Yoshida, S, Arner, P, Axton, RA, Babina, M, Baillie, JK, Barnett, TC, Beckhouse, AG, Blumenthal, A, Bodega, B, Bonetti, A, Briggs, J, Brombacher, F, Carlisle, AJ, Clevers, HC, Davis, CA, Detmar, M, Dohi, T, Edge, ASB, Edinger, M, Ehrlund, A, Ekwall, K, Endoh, M, Enomoto, H, Eslami, A, Fagiolini, M, Fairbairn, L, Farach-Carson, MC, Faulkner, GJ, Ferrai, C, Fisher, ME, Forrester, LM, Fujita, R, Furusawa, J-I, Geijtenbeek, TB, Gingeras, T, Goldowitz, D, Guhl, S, Guler, R, Gustincich, S, Ha, TJ, Hamaguchi, M, Hara, M, Hasegawa, Y, Herlyn, M, Heutink, P, Hitchens, KJ, Hume, DA, Ikawa, T, Ishizu, Y, Kai, C, Kawamoto, H, Kawamura, YI, Kempfle, JS, Kenna, TJ, Kere, J, Khachigian, LM, Kitamura, T, Klein, S, Klinken, SP, Knox, AJ, Kojima, S, Koseki, H, Koyasu, S, Lee, W, Lennartsson, A, Mackay-sim, A, Mejhert, N, Mizuno, Y, Morikawa, H, Morimoto, M, Moro, K, Morris, KJ, Motohashi, H, Mummery, CL, Nakachi, Y, Nakahara, F, Nakamura, T, Nakamura, Y, Nozaki, T, Ogishima, S, Ohkura, N, Ohno, H, Ohshima, M, Okada-Hatakeyama, M, Okazaki, Y, Orlando, V, Ovchinnikov, DA, Passier, R, Patrikakis, M, Pombo, A, Pradhan-Bhatt, S, Qin, X-Y, Rehli, M, Rizzu, P, Roy, S, Sajantila, A, Sakaguchi, S, Sato, H, Satoh, H, Savvi, S, Saxena, A, Schmidl, C, Schneider, C, Schulze-Tanzil, GG, Schwegmann, A, Sheng, G, Shin, JW, Sugiyama, D, Sugiyama, T, Summers, KM, Takahashi, N, Takai, J, Tanaka, H, Tatsukawa, H, Tomoiu, A, Toyoda, H, van de Wetering, M, van den Berg, LM, Verardo, R, Vijayan, D, Wells, CA, Winteringham, LN, Wolvetang, E, Yamaguchi, Y, Yamamoto, M, Yanagi-Mizuochi, C, Yoneda, M, Yonekura, Y, Zhang, PG, Zucchelli, S, Abugessaisa, I, Arner, E, Harshbarger, J, Kondo, A, Lassmann, T, Lizio, M, Sahin, S, Sengstag, T, Severin, J, Shimoji, H, Suzuki, M, Suzuki, H, Kawai, J, Kondo, N, Itoh, M, Daub, CO, Kasukawa, T, Kawaji, H, Carninci, P, Forrest, ARR, and Hayashizaki, Y

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

8. The statistical geometry of transcriptome divergence in cell-type evolution and cancer

Author

Liang, C, Alam, I, Albanese, D, Altschuler, G, Andersson, R, Arakawa, T, Archer, J, Arner, E, Arner, P, Babina, M, Baillie, K, Bajic, V, Baker, S, Balic, A, Balwierz, P, Beckhouse, A, Bertin, N, Blake, Ja, Blumenthal, A, Bodega, B, Bonetti, A, Briggs, J, Brombacher, F, Burroughs, M, Califano, A, Cannistraci, C, Carbajo, D, Carninci, P, Chen, Yang, Chierici, M, Ciani, Y, Clevers, H, Dalla, Emiliano, Daub, C, Davis, C, De Hoon, M, De Lima Morais, D, Dermar, M, Diehl, A, Dimont, E, Dohl, T, Drabros, F, Edge, A, Edinger, M, Ekwall, K, Endoh, M, Enomoto, H, Fagiolini, M, Fairbairn, L, Fang, H, Farach Carson, Mc, Faulkner, G, Favorov, A, Fisher, M, Forrest, A, Francescatto, M, Freeman, T, Frith, M, Fujita, R, Fukuda, S, Furlanello, C, Furuno, M, Furusawa, J, Geijtenbeek, Tb, Gibson, A, Gingeras, T, Goldowithz, D, Gough, J, Guhl, S, Guler, R, Gustincich, Stefano, Ha, T, Haberle, V, Hamaguchi, M, Hara, M, Harbers, M, Harshbarger, J, Hasegawa, A, Hasegawa, Y, Hashimoto, T, Hayashizaki, Y, Herlyn, M, Heutink, P, Hide, W, Hitchens, K, Ho Sui, S, Hofmann, O, Hoof, I, Hori, F, Hume, D, Huminiecki, L, Iida, K, Ikawa, T, Ishizu, Y, Itoh, M, Jankovic, B, Jia, H, Jorgensen, M, Joshi, A, Jurman, G, Kaczkowski, B, Kai, C, Kaida, K, Kaiho, A, Kajiyama, K, Kanamori Katayama, M, Kasianov, A, Kasukawa, T, Katayama, S, Kato Ishikawa, S, Kawaguchi, S, Kawai, J, Kawaji, H, Kawamoto, H, Kawamura, Y, Kawashima, T, Kempfle, J, Kenna, T, Kere, J, Khachigian, L, Kitamura, T, Klinken, P, Knox, A, Kojima, M, Kojima, S, Kondo, N, Koseki, H, Koyasu, S, Krampitz, S, Kubosaki, A, Kulakovskiy, I, Kwon, At, Laros, J, Lassmann, T, Lenhard, B, Lennartsson, A, Li, K, Lilji, B, Lipovich, L, Lizio, M, Mackay Sim, A, Makeev, V, Manabe, R, Mar, J, Marchand, B, Mathelier, A, Medvedeva, Y, Meehan, Tf, Mejhert, N, Meynert, A, Mizuno, Y, Morikawa, H, Morimoto, M, Moro, K, Motakis, E, Motohashi, H, Mummery, C, Mungall, Cj, Murata, M, Nagao Sato, S, Nakachi, Y, Nakahara, F, Nakamura, T, Nakamura, Y, Nakazato, K, Ninomiya Fukuda, N, Nishiyori Sueki, H, Noma, S, Nozaki, T, Ogishima, S, Ohkura, N, Ohmiya, H, Ohno, H, Ohshima, M, Okada Hatakeyama, M, Okazaki, Y, Orlando, V, Ovchinnikov, D, Pain, A, Passier, R, Persson, H, Piazza, Silvano, Plessy, C, Pradhan Bhatt, S, Prendergast, J, Rackham, O, Ramilowski, J, Rashid, M, Ravasi, T, Rehli, M, Rizzu, P, Roncador, M, Roy, S, Rye, M, Saijyo, E, Sajantila, A, Saka, A, Sakaguchi, S, Sakai, M, Sandelin, A, Sato, H, Satoh, H, Suzana, S, Alka, S, Schaefer, U, Schmeier, S, Schmidl, C, Schneider, C, Schultes, Ea, Schulze Tanzil, G, Schwegmann, A, Semple, C, Sengstag, T, Severin, J, Sheng, G, Shimoji, H, Shimoni, Y, Shin, J, Simon, C, Sugiyama, D, Sugiyama, T, Summers, K, Suzuki, H, Suzuki, M, Suzuki, N, Swoboda, R, Hoen P, T, Tagami, M, Takahashi, N, Takai, J, Tanaka, H, Tatsukawa, H, Tatum, Z, Taylor, M, Thompson, M, Toyoda, H, Toyoda, T, Valen, E, Van De Wetering, M, Van Den Berg, L, Van Nimwegen, E, Verardo, R, Vijayan, D, Vitezic, M, Vorontzov, I, Wasserman, W, Watanabe, S, Wells, C, Winteringham, L, Wolvetang, E, Wood, Ej, Yamaguchi, Y, Yamamoto, M, Yoneda, M, Yonekura, Y, Yoshida, Shin'Ichirou, Young, R, Zabierowski, Se, Zhang, P, Zhao, X, Zucchelli, Silvia, Forrest, Ar, Wagner, Gp, Hubrecht Institute for Developmental Biology and Stem Cell Research, AII - Amsterdam institute for Infection and Immunity, Infectious diseases, and Experimental Immunology

Subjects
Cell type, General Physics and Astronomy, rna-seq data, phylogenetic networks, Biology, ENCODE, General Biochemistry, Genetics and Molecular Biology, Divergence, Transcriptome, Models, Settore BIO/13 - Biologia Applicata, Neoplasms, Humans, Genetics, Models, Statistical, Multidisciplinary, Statistical model, General Chemistry, Statistical, Biological Evolution, Body plan, Tree structure, Evolutionary biology, Cancer cell
Abstract

In evolution, body plan complexity increases due to an increase in the number of individualized cell types. Yet, there is very little understanding of the mechanisms that produce this form of organismal complexity. One model for the origin of novel cell types is the sister cell-type model. According to this model, each cell type arises together with a sister cell type through specialization from an ancestral cell type. A key prediction of the sister cell-type model is that gene expression profiles of cell types exhibit tree structure. Here we present a statistical model for detecting tree structure in transcriptomic data and apply it to transcriptomes from ENCODE and FANTOM5. We show that transcriptomes of normal cells harbour substantial amounts of hierarchical structure. In contrast, cancer cell lines have less tree structure, suggesting that the emergence of cancer cells follows different principles from that of evolutionary cell-type origination.

Published
2015
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9. Differential roles of epigenetic changes and Foxp3 expression in regulatory T cell-specific transcriptional regulation

Author

Morikawa, H, Ohkura, N, Vandenbon, A, Itoh, M, Nagao Sato, S, Kawaji, H, Lassmann, T, Carninci, P, Hayashizaki, Y, Forrest, Ar, Standley, Dm, Date, H, Sakaguchi, S, FANTOM Consortium (Forrest AR, Rehli, M, Baillie, Jk, de Hoon MJ, Haberle, V, Kulakovskiy, Iv, Lizio, M, Andersson, R, Mungall, Cj, Meehan, Tf, Schmeier, S, Bertin, N, Jørgensen, M, Dimont, E, Arner, E, Schmidl, C, Schaefer, U, Medvedeva, Ya, Plessy, C, Vitezic, M, Severin, J, Semple, Ca, Ishizu, Y, Francescatto, M, Alam, I, Albanese, D, Altschuler, Gm, Archer, Ja, Arner, P, Babina, M, Baker, S, Balwierz, Pj, Beckhouse, Ag, Pradhan Bhatt, S, Blake, Ja, Blumenthal, A, Bodega, B, Bonetti, A, Briggs, J, Brombacher, F, Burroughs, Am, Califano, A, Cannistraci, Cv, Carbajo, D, Chen, Y, Chierici, M, Ciani, Y, Clevers, Hc, Dalla, E, Davis, Ca, Deplancke, B, Detmar, M, Diehl, Ad, Dohi, T, Drabløs, F, Edge, As, Edinger, M, Ekwall, K, Endoh, M, Enomoto, H, Fagiolini, M, Fairbairn, L, Fang, H, Farach Carson MC, Faulkner, Gj, Favorov, Av, Fisher, Me, Frith, Mc, Fujita, R, Fukuda, S, Furlanello, C, Furuno, M, Furusawa, J, Geijtenbeek, Tb, Gibson, A, Gingeras, T, Goldowitz, D, Gough, J, Guhl, S, Guler, R, Gustincich, Stefano, Ha, Tj, Hamaguchi, M, Hara, M, Harbers, M, Harshbarger, J, Hasegawa, A, Hasegawa, Y, Hashimoto, T, Herlyn, M, Hitchens, Kj, Ho Sui SJ, Hofmann, Om, Hoof, I, Hori, F, Huminiecki, L, Iida, K, Ikawa, T, Jankovic, Br, Jia, H, Joshi, A, Jurman, G, Kaczkowski, B, Kai, C, Kaida, K, Kaiho, A, Kajiyama, K, Kanamori Katayama, M, Kasianov, As, Kasukawa, T, Katayama, S, Kato, S, Kawaguchi, S, Kawamoto, H, Kawamura, Yi, Kawashima, T, Kempfle, Js, Kenna, Tj, Kere, J, Khachigian, Lm, Kitamura, T, Klinken, Sp, Knox, Aj, Kojima, M, Kojima, S, Kondo, N, Koseki, H, Koyasu, S, Krampitz, S, Kubosaki, A, Kwon, At, Laros, Jf, Lee, W, Lennartsson, A, Li, K, Lilje, B, Lipovich, L, Mackay Sim, A, Manabe, R, Mar, Jc, Marchand, B, Mathelier, A, Mejhert, N, Meynert, A, Mizuno, Y, Morais, Da, Morimoto, M, Moro, K, Motakis, E, Motohashi, H, Mummery, Cl, Murata, M, Nakachi, Y, Nakahara, F, Nakamura, T, Nakamura, Y, Nakazato, K, van Nimwegen, E, Ninomiya, N, Nishiyori, H, Noma, S, Nozaki, T, Ogishima, S, Ohmiya, H, Ohno, H, Ohshima, M, Okada Hatakeyama, M, Okazaki, Y, Orlando, V, Ovchinnikov, Da, Pain, A, Passier, R, Patrikakis, M, Persson, H, Piazza, S, Prendergast, Jg, Rackham, Oj, Ramilowski, Ja, Rashid, M, Ravasi, T, Rizzu, P, Roncador, M, Roy, S, Rye, Mb, Saijyo, E, Sajantila, A, Saka, A, Sakai, M, Sato, H, Satoh, H, Savvi, S, Saxena, A, Schneider, C, Schultes, Ea, Schulze Tanzil GG, Schwegmann, A, Sengstag, T, Sheng, G, Shimoji, H, Shimoni, Y, Shin, Jw, Simon, C, Sugiyama, D, Sugiyama, T, Suzuki, M, Swoboda, Rk, 't Hoen PA, 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 LM, Verardo, R, Vijayan, D, Vorontsov, Ie, Wasserman, Ww, Watanabe, S, Wells, Ca, Winteringham, Ln, Wolvetang, E, Wood, Ej, Yamaguchi, Y, Yamamoto, M, Yoneda, M, Yonekura, Y, Yoshida, S, Zabierowski, Se, Zhang, Pg, Zhao, X, Zucchelli, S, Summers, Km, Suzuki, H, Daub, Co, Kawai, J, Heutink, P, Hide, W, Freeman, Tc, Lenhard, B, Bajic, Vb, Taylor, Ms, Makeev, Vj, Sandelin, A, Hume, Da, Hayashizaki, Y., AII - Amsterdam institute for Infection and Immunity, Infectious diseases, Experimental Immunology, and Hubrecht Institute for Developmental Biology and Stem Cell Research

Subjects
Transcription, Genetic, Regulatory T cell, T-Lymphocytes, Down-Regulation, chemical and pharmacologic phenomena, Biology, Inbred C57BL, T-Lymphocytes, Regulatory, Epigenesis, Genetic, Mice, Genetic, Settore BIO/13 - Biologia Applicata, medicine, Transcriptional regulation, Animals, Epigenetics, Gene, Inbred BALB C, Genetics, Regulation of gene expression, Mice, Inbred BALB C, Multidisciplinary, Binding Sites, FOXP3, hemic and immune systems, Forkhead Transcription Factors, DNA Methylation, Biological Sciences, Regulatory, Cap analysis gene expression, Mice, Inbred C57BL, medicine.anatomical_structure, Gene Expression Regulation, DNA methylation, Transcription, Epigenesis
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
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11. Langerhans cell antigen capture through tight junctions confers preemptive immunity in experimental staphylococcal scalded skin syndrome

Author

Ouchi, T. (Takeshi), Kubo, A. (Akiharu), Yokouchi, M. (Mariko), Adachi, T. (Takeya), Kobayashi, T. (Tetsuro), Kitashima, D.Y. (Daniela), Fujii, H. (Hideki), Clausen, B.E. (Bjorn), Koyasu, S. (Shigeo), Amagai, M. (Masayuki), Nagao, K. (Keisuke), Ouchi, T. (Takeshi), Kubo, A. (Akiharu), Yokouchi, M. (Mariko), Adachi, T. (Takeya), Kobayashi, T. (Tetsuro), Kitashima, D.Y. (Daniela), Fujii, H. (Hideki), Clausen, B.E. (Bjorn), Koyasu, S. (Shigeo), Amagai, M. (Masayuki), and Nagao, K. (Keisuke)

Abstract

Epidermal Langerhans cells (LCs) extend dendrites through tight junctions (TJs) to survey the skin surface, but their immunological contribution in vivo remains elusive. We show that LCs were essential for inducing IgG1 responses to patch-immunized ovalbumin in mice that lacked skin dendritic cell subsets. The significance of LC-induced humoral responses was demonstrated in a mouse model of staphylococcal scalded skin syndrome (SSSS), a severe blistering disease in which the desmosomal protein Dsg1 (desmoglein1) is cleaved by Staphylococcus aureus-derived exfoliative toxin (ET). Importantly, ET did not penetrate TJs, and patch immunization did not alter epidermal integrity. Nevertheless, neutralizing anti- ET IgG 1 was induced after patch immunization and abolished upon LC depletion, indicating that antigen capture through TJs by LCs induced humoral immunity. Strikingly, the ET-patched mice were protected from developing SSSS after intraperitoneal ET challenge, whereas LCdepleted mice were susceptible to SSSS, demonstrating a vital role for LC-induced IgG1 in systemic defense against circulating toxin in vivo. Therefore, LCs elicit humoral immunity to antigens that have not yet violated the epidermal barrier, providing preemptive immunity against potentially pathogenic skin microbes. Targeting this immunological process confers protection with minimal invasiveness and should have a marked impact on future strategies for development of percutaneous vaccines.

Published
2011
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17. SPECIFIC ROLES OF PHOSPHOINOSITIDE 3-KINASE ISOFORMS ALPHA AND BETA IN GLYCOPROTEIN VI-INDUCED PLATELET SIGNALING TO PROCOAGULANT ACTIVITY

Author

Munnix, I.C.A., primary, Cosemans, J.M.E.M., additional, van der Meijden, P.E.J., additional, van Montfoort, A.P.A., additional, Feijge, M.A.H., additional, Farndale, R.W., additional, Koyasu, S., additional, Heller, R., additional, Sage, S.O., additional, Jackson, S.P., additional, and Heemskerk, J.W.M., additional

Published
2007
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38. Temperature-sensitive ZAP70 mutants degrading through a proteasome-independent pathway. Restoration of a kinase domain mutant by Cdc37.

Author

Matsuda, S, Suzuki-Fujimoto, T, Minowa, A, Ueno, H, Katamura, K, and Koyasu, S

Abstract

CD8 deficiency is an autosomal recessive form of severe combined immunodeficiency diseases characterized by the absence of CD8(+) T lymphocytes and impaired T cell functions. We identified two novel mis-sense mutations in the zap70 genes of a CD8-deficiency patient. One mutation (P80Q) affects a residue in an SH2 domain and another (M572L) in the kinase subdomain XI. Both mutations cause a degradation of ZAP70 protein in a temperature-sensitive manner through an ATP-dependent and proteasome-independent pathway. We further demonstrated that Cdc37, a protein kinase-specific chaperone, bound to M572L but not P80Q mutant and restored the expression of the M572L mutant when overexpressed. The restoration of M572L mutant by Cdc37 required the function of HSP90. These results indicate that Cdc37 in conjunction with HSP90 functions as a molecular chaperone for a temperature-sensitive kinase domain mutant of ZAP70.

Published
1999

39. Interleukin 3‐specific tyrosine phosphorylation of a membrane glycoprotein of Mr 150,000 in multi‐factor‐dependent myeloid cell lines.

Author

Koyasu, S., Tojo, A., Miyajima, A., Akiyama, T., Kasuga, M., Urabe, A., Schreurs, J., Arai, K., Takaku, F., and Yahara, I.

Abstract

Tyrosine phosphorylation of cellular proteins induced by various hematopoietic growth factors such as interleukin 3 (IL3), granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) and interleukin 4 (IL4) was studied in several multi‐factor‐dependent myeloid cell lines. Among the growth factors, IL3 specifically induced rapid tyrosine phosphorylation of a membrane glycoprotein of mol. wt 150 kd (gpp150) in the IL3‐dependent cell lines, IC2 and DA‐1. The IL3‐induced tyrosine phosphorylation of gpp150 was detected within 30 s, reached a maximum at 3 min and decreased thereafter. The concentration of IL3 required for half‐maximum stimulation of gpp150 tyrosine phosphorylation with 2.5 x 10(6)/ml cells was approximately 200 pM, which is the same as the dissociation constant for 125I‐labeled IL3 binding. gpp150 was constitutively phosphorylated on tyrosine residue(s) in growth factor independent variants, IC2Tr and DA‐1Tr, derived from IC2 and DA‐1 respectively. Neither variant synthesized IL3. The present findings suggest that tyrosine phosphorylation of gpp150 is a critical event involved in both IL3‐dependent and ‐independent growth.

Published
1987
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40. T lymphocyte activation signals for interleukin-2 production involve activation of MKK6-p38 and MKK7-SAPK/JNK signaling pathways sensitive to cyclosporin A.

Author

Matsuda, S, Moriguchi, T, Koyasu, S, and Nishida, E

Abstract

p38/CSBP, a subgroup member of mitogen-activated protein kinase (MAPK) superfamily molecules, is known to be activated by proinflammatory cytokines and environmental stresses. We report here that p38 is specifically activated by signals that lead to interleukin-2 (IL-2) production in T lymphocytes. A p38 activator MKK6 was also markedly activated by the same stimulation. Pretreatment of cells with SB203580, a specific inhibitor of p38, as well as expression of a dominant-negative mutant of MKK6, suppressed the transcriptional activation of the IL-2 promoter. We also demonstrated that MKK7, a recently described MAPK kinase family member, plays a major role in the activation of stress-activated protein kinase (SAPK)/c-Jun NH2-terminal kinase (JNK) in T lymphocytes. Moreover, a dominant-negative mutant of MKK7 abrogated the transcriptional activation of the distal nuclear factor of activated T cells response element in the IL-2 promoter. Cyclosporin A, a potent immunosuppressant, inhibited activation of both p38 and SAPK/JNK pathways but not the MAPK/extracellular signal-regulated kinase (ERK) pathway. Our results indicate that both MKK6 to p38 and MKK7 to SAPK/JNK signaling pathways are activated in a cyclosporin A-sensitive manner and contribute to IL-2 gene expression in T lymphocytes.

Published
1998

41. Two mammalian heat shock proteins, HSP90 and HSP100, are actin-binding proteins.

Author

Koyasu, S, Nishida, E, Kadowaki, T, Matsuzaki, F, Iida, K, Harada, F, Kasuga, M, Sakai, H, and Yahara, I

Abstract

Two high molecular weight heat shock proteins, HSP90 (Mr, 90,000) and HSP100 (Mr, 100,000), were separately purified from extracts of cultured cells of a mouse lymphoma cell line, L5178Y. Both of the HSPs exist in homodimeric form under physiological conditions. Their physicochemical properties are quite similar to each other. Each of the purified HSPs was shown to coprecipitate with rabbit skeletal muscle actin under actin-polymerizing conditions. Both HSP90 and HSP100 increased the low-shear viscosity of filamentous actin solutions in a dose-dependent manner, which suggests that these HSPs cross-link actin filaments. Although some molecular properties and the effects described above on actin solution of HSP90 and HSP100 resemble those of alpha-actinin, the HSPs were distinguished from alpha-actinin by various means, including visualization of molecular shapes by electron microscopy with the aid of the low-angle rotary shadowing technique. Immunofluorescence staining by specific antisera against HSP90 revealed that HSP90 was localized in ruffling membranes in addition to the cytoplasmic space.

Published
1986
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42. Insulin-like growth factors, insulin, and epidermal growth factor cause rapid cytoskeletal reorganization in KB cells. Clarification of the roles of type I insulin-like growth factor receptors and insulin receptors.

Author

Kadowaki, T, Koyasu, S, Nishida, E, Sakai, H, Takaku, F, Yahara, I, and Kasuga, M

Abstract

Insulin-like growth factor (IGF) I (greater than or equal to 10(-10)M, insulin-like growth factor II (greater than or equal to 10(-9) M), insulin (greater than or equal to 10(-9) M, and epidermal growth factor (EGF, greater than or equal to 10(-11) M) caused rapid membrane ruffling in KB cells. The morphological change was observed within 1 min after the addition of these growth factors and was accompanied by microfilament reorganization, but not by microtubule reorganization. IGF-I, IGF-II, and insulin induced morphologically very similar or identical membrane ruffles with the order of potency IGF-I greater than IGF-II greater than insulin, whereas EGF-induced membrane ruffles were morphologically different. KB cells possessed EGF receptors, type I IGF receptors, and insulin receptors, but few or no type II IGF receptors. Monoclonal antibody against type I IGF receptors, which completely inhibited the binding of 125I-IGF-I to the cells but did not inhibit the binding of 125I-insulin, caused marked inhibition of IGF-I (10(-8) M)-stimulated membrane ruffling. IGF-II (10(-8) M)-stimulated membrane ruffling was partially inhibited in the presence of this antibody, but insulin (10(-7) M)-stimulated membrane ruffling was only slightly inhibited. In contrast, monoclonal antibody against insulin receptors blocked insulin (10(-7) M) stimulation, but not IGF-I (10(-8) M) stimulation, of membrane ruffling. Thus, this study provides evidence that IGF-I and insulin act mostly through their own (homologous) receptors and that IGF-II acts by cross-reacting with both type I IGF and insulin (heterologous) receptors in causing rapid alterations in cytoskeletal structure.

Published
1986
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43. Calmodulin-regulated binding of the 90-kDa heat shock protein to actin filaments.

Author

Nishida, E, Koyasu, S, Sakai, H, and Yahara, I

Abstract

We have found that the 90-kDa heat shock protein (HSP90) prepared from a mouse lymphoma exists in homodimeric form under physiological conditions and has the ability to bind to F-actin (Koyasu, S., Nishida, E., Kadowaki, T., Matsuzaki, F., Iida, K., Harada, F., Kasuga, M., Sakai, H., and Yahara, I. (1986) Proc. Natl. Acad. Sci. U.S.A., in press). Here we show that calmodulin regulates the binding of HSP90 to F-actin in a Ca2+-dependent manner. The binding of HSP90 to F-actin occurred optimally under physiological solution conditions, i.e. in 2 mM MgCl2 + 100 mM KCl. The binding was saturable in a molar ratio of about 1 HSP90 (dimer) to 10 actins. HSP90 was dissociated from F-actin by the binding of tropomyosin to F-actin. Calmodulin was found to inhibit the binding of HSP90 to F-actin in a Ca2+-dependent manner. Moreover, the equilibrium gel filtration demonstrated that calmodulin binds to HSP90 in the presence of Ca2+, but not in the absence of Ca2+. These data indicate that HSP90 complexed with Ca2+-calmodulin is unable to bind to F-actin. Ca2+-dependent interaction of HSP90 with calmodulin as well as calmodulin-regulated binding of HSP90 to F-actin revealed here may provide new insight into the function of HSP90 and the regulation of actin structure in cells.

Published
1986
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44. Tyrosine phosphorylation of common and specific sets of cellular proteins rapidly induced by insulin, insulin-like growth factor I, and epidermal growth factor in an intact cell.

Author

Kadowaki, T, Koyasu, S, Nishida, E, Tobe, K, Izumi, T, Takaku, F, Sakai, H, Yahara, I, and Kasuga, M

Abstract

KB cells respond to insulin and insulin-like growth factor I (IGF-I) in a closely similar way (induction of membrane ruffling, stimulation of pinocytosis, and amino acid transport) but respond to epidermal growth factors (EGF) in a similar but distinct way. In the KB cells, using phosphotyrosine-specific antibody we have found that: the receptors for insulin (beta subunit), IGF-I (beta subunit), and EGF undergo tyrosine phosphorylation as early as 10 s after addition of their respective ligands; a 185-kDa protein is rapidly (less than 10 s) tyrosine phosphorylated by insulin and IGF-I through their respective receptor kinases but not EGF; tyrosine phosphorylation of a 190-kDa glycoprotein is rapidly (less than 10 s) induced by EGF through EGF receptor kinase; and tyrosine phosphorylation of a 240-kDa protein is stimulated within 30 s by all three growth factors. These patterns of tyrosine phosphorylation could be causally related to biological responses induced by the three growth factors.

Published
1987
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45. Cofilin is a component of intranuclear and cytoplasmic actin rods induced in cultured cells.

Author

Nishida, E, Iida, K, Yonezawa, N, Koyasu, S, Yahara, I, and Sakai, H

Abstract

Incubation of cultured cells under specific conditions induces a dramatic change in the actin organization: induction of intranuclear and/or cytoplasmic actin rods (actin paracrystal-like intracellular structures). We have found that cofilin, a 21-kDa actin-binding protein, is a component of these rods. Antibodies directed against cofilin labeled intranuclear actin rods induced in cells treated with dimethyl sulfoxide or exposed to heat shock and also labeled cytoplasmic actin rods induced in cells incubated in specific salt buffers. Moreover, we found that these actin rods are not stained with fluorescent phalloidin derivatives at all and appear to be right-handed helices, different from straight bundles of F-actin such as stress fibers. In vitro experiments revealed that cofilin and phalloidin compete with each other for binding to F-actin. Since cofilin and phalloidin have the ability to stoichiometrically bind actin molecule in the filament in vitro, the above results seem to suggest that cofilin directly binds to actin molecule in nearly an equimolar ratio in these rods. We call these rods "actin/cofilin rods."

Published
1987
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46. Protein Kinase C-dependent and -independent Pathways in the Growth Factor-induced Cytoskeletal Reorganization*

Author

Miyata, Y, Nishida, E, Koyasu, S, Yahara, I, and Sakai, H

Abstract

Human epidermoid carcinoma KB cells exhibit rapid induction of membrane ruffling in response to epidermal growth factor (EGF), insulin, and insulin-like growth factor-I (IGF-I) (Kadowaki, T., Koyasu, S., Nishida, E., Sakai, H., Takaku, F., Yahara, I., and Kasuga.M. (1986) J. Biol. Chem. 261,16141–16147). We have analyzed the role of protein kinase C (PKC) in this response. Treatment of KB cells with 4β-phorbol 12,13-dibutyrate (PDBu) (100 ng/ml) for 30 min caused translocation of PKC to the membrane. This treatment completely inhibited the induction of membrane ruffling by EGF, insulin, and IGF-I. Prolonged treatment with PDEtu (200 ng/ml for 15 h) induced complete depletion of the PKC activity in the cells. Under these conditions, EGF binding to cells and autophosphorylation of the EGF receptor occurred normally, while EGF could not induce membrane ruffling. In contrast, insulin- or IGF-I-induced membrane ruffling occurred normally in the PKC-depleted cells. Moreover, H-7 (PKC inhibitor) inhibited only EGF-induced membrane ruffling in a dose-dependent manner. We further found that EGF, but not insulin/IGF-I, caused transient translocation of PKC to the membrane. All these results suggest that PKC is required for the membrane ruffling induced by EGF but not for that induced by insulin/IGF-I. Therefore, there are PKC-dependent and independent pathways in the growth factor-induced membrane ruffling. Furthermore, we propose dual roles of PKC in the EGF signaling, a signal transmitting role and a negative feedback role.

Published
1989
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47. Signals for activation and proliferation of murine T lymphocyte clones.

Author

Koyasu, S., Suzuki, G., Asano, Y., Osawa, H., Diamantstein, T., and Yahara, I.

Abstract

Biochemical signals required for the growth of T cell clones were studied. Antigen-specific helper T cell clones, 6-1 and KO.6, could enter the state similar to the resting state where the cells expressed only small numbers of interleukin 2 (IL2) receptors and could not respond to IL2 without antigenic stimulation. A combination of a phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), and a calcium ionophore, A23187, induced the expression of IL2 receptors on resting 6-1 cells and induced DNA synthesis in the presence of IL2. TPA alone did not induce IL2 receptors. A23187 induced the expression of the receptors to some extent but did not induce DNA synthesis even in the presence of IL2. IL2 receptors induced by A23187 alone were mostly low affinity receptors, whereas the combination of TPA and A23187 induced high affinity receptors in addition to low affinity receptors. Resting KO.6 cells produced IL2 in response to a combination of TPA and A23187, whereas either one of the agents did not induce the production of IL2. Dicaprylin, a permeable diacylglycerol and a potent activator of protein kinase C (the Ca2+/phospholipid-dependent enzyme) could replace TPA in both cases when dicaprylin was repeatedly added to the culture. These results suggest that strong and continuous activation of protein kinase C together with calcium mobilization is required for IL2 production and IL2 receptor expression. On the contrary, signals for DNA synthesis generated by binding of IL2 to IL2 receptors are different from those for IL2 production and IL2 receptor expression, as the combination of TPA and A23187 could not induce DNA synthesis without IL2.

Published
1987
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48. IL-2 and IL-7 differentially induce CD4-CD8- alpha beta TCR+NK1.1+ large granular lymphocytes and IL-4-producing cells from CD4-CD8- alpha beta TCR+NK1.1- cells: implications for the regulation of Th1- and Th2-type responses.

Author

Nishizawa, K and Koyasu, S

Abstract

Effector functions of CD4-CD8- double negative (DN) alpha beta TCR+ cells were examined. Among mouse DN alpha beta TCR+ thymocytes, NK1.1+ cells expressing a canonical V alpha 14/J alpha 281 TCR but not NK1.1- cells produce IL-4 upon TCR cross-linking and IFN-gamma upon cross-linking of NK1.1 as well as TCR. Production of IL-4 but not IFN-gamma from DN alpha beta TCR+NK1.1+ cells was markedly suppressed by IL-2. Whereas V alpha 14/J alpha 281 TCR+ cells express NK1.1+, these cells are not the precursor of DN alpha beta TCR+NK1.1+CD16+B220+ large granular lymphocytes (LGL). IL-2 induces rapid proliferation and generation of NK1.1+ LGL from DN alpha beta TCR+NK1.1- but not from DN alpha beta TCR+NK1.1+ cells. LGL cells exhibit NK activity and produce IFN-gamma but not IL-4 upon cross-linking of surface TCR or NK1.1 molecules. In contrast to IL-2, IL-7 does not induce LGL cells or NK activity from DN alpha beta TCR+NK1.1- cells but induces the ability to produce high levels of IL-4 upon TCR cross-linking. Our results show that DN alpha beta TCR+ T cells have several distinct subpopulations, and that IL-2 and IL-7 differentially regulate the functions of DN alpha beta TCR+ T cells by inducing different types of effector cells.

Published
1997
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49. HSP100, a 100-kDa Heat Shock Protein, is a Ca2+-Calmodulin-regulated Actin-binding Protein

Author

Koyasu, S, Nishida, E, Miyata, Y, Sakai, H, and Yahara, I

Abstract

The 100-kDa heat shock protein, HSP100, was purified from mouse lymphoma cells. Amino acid sequences of three peptide fragments which were obtained from the purified protein by lysylendopeptidase digestion were completely or nearly identical with those of a mouse endoplasmic reticulum protein, ERp99, of a hamster glucose-regulated protein, GRP94, and of a chicken heat shock protein, HSP108, all of which have been known to have strong homology with the 90-kDa heat shock protein, HSP90. HSP100 bound to actin filaments and an apparent Kdfor the binding was determined to be 8 × 10−7M in 2 mMMgCl2+ 100 mMKCl. Calmodulin inhibited the binding in a Ca2+-dependent manner. Equilibrium gel filtration demonstrated that HSP100 has an ability to bind to calmodulin only in the presence of Ca2+. Moreover, HSP100 competed with HSP90 for binding to actin filaments. These results together with our previous findings that HSP90 and HSP100 have similar physicochemical properties (Koyasu, S., Nishida, E., Kadowaki, T., Matsuzaki, F., Iida, K., Harada, F., Kasuga, M., Sakai, H., and Yahara, I. (1986) Proc. Natl. Acad. Sci. U.S.A.83, 8054–8058) and HSP90 is a calmodulin-regulated actin-binding protein (Nishida, E., Koyasu, S., Sakai, H., and Yahara, I. (1986) J. Biol. Chem. 261, 16033–16036), strongly suggest that HSP100 is structurally and functionally related to HSP90.

Published
1989
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50. Regulation of polar morphogenesis in Caulobacter crescentus

Author

Fukuda, A, Asada, M, Koyasu, S, Yoshida, H, Yaginuma, K, and Okada, Y

Abstract

Deoxyribonucleic acid (DNA) phage phi CbK-resistant nonmotile mutants of Caulobacter crescentus CB15 were examined for their formation of polar surface structures (a stalk, a single flagellum, pili, and DNA phage receptors). These mutants were devoid of pili and DNA phage receptors and simultaneously defective either in both stalk formation and flagellar activity (stalk-defective type) or in the formation of normal flagella (flagella-defective type). DNA phage phi Cr30-mediated transductions revealed that stalk-defective mutants were of a single genetic type, whereas flagella-defective mutants were grouped into two different genetic types, I and II. To investigate how membrane proteins change in the above morphology mutants, cell envelopes pulse-labeled with L-[35S]methionine were analyzed by two-dimensional gel electrophoresis. No gross change of membrane proteins was observed in the stalk-defective mutant CB15 pdr-803, except a 49,000-molecular-weight (49K) protein which was found reduced. However, a 27K, two 28.5K, and a 70.5K protein were missing from the membrane of the flagella-defective type I mutant CB15 pdr-813. These proteins are most likely to be flagella-related protein, flagellins A and B, and hook protein, respectively. In another flagella-defective type II mutant, CB15 pdr-816, the 27K and two 28.5K proteins were similarly absent but the 70.5K protein was consistently present in the membrane. The synthesis of flagellin was next assayed radioimmunologically in the above 35S-labeled mutants. Stalk-defective CB15 pdr-803 synthesized flagellin normally, compared to the wild-type strain. Flagellins A (26K) and B (28K) formed multiple spots in isoelectric focusing. A 29K protein was also detected in the flagellin-specific radioactivity from the cytoplasm. Flagella-defective type I CB15 pdr-813 synthesized flagellin only at a basal level. Thus transcription or translation of flagellin appeared to be repressed in this mutant. Another flagella-defective type II strain, CB15 pdr-816, however, synthesized flagellin at an apparently enhanced rate compared with the wild type. Flagellin synthesized in CB15 pdr-816 was flagellin A and a smaller 22K flagellin. Flagellin B was not synthesized in the mutant. It then follows that flagellin B is not a precursor of flagellin A and the 22K flagellin. Flagella-defective type II CB15 pdr-816, without flagellin B, formed a stub structure with a hook attached to one end instead of normal flagella. In the wild-type membrane, flagellin B was the major flagellin, whereas flagellin A was major in the cytoplasm and the flagellar filament. It is suggested from these results that flagellin B is important in the assembly of normal flagella.

Published
1981
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