Article | Published:

The transcriptional network that controls growth arrest and differentiation in a human myeloid leukemia cell line

Nature Genetics volume 41, pages 553562 (2009) | Download Citation

Abstract

Using deep sequencing (deepCAGE), the FANTOM4 study measured the genome-wide dynamics of transcription-start-site usage in the human monocytic cell line THP-1 throughout a time course of growth arrest and differentiation. Modeling the expression dynamics in terms of predicted cis-regulatory sites, we identified the key transcription regulators, their time-dependent activities and target genes. Systematic siRNA knockdown of 52 transcription factors confirmed the roles of individual factors in the regulatory network. Our results indicate that cellular states are constrained by complex networks involving both positive and negative regulatory interactions among substantial numbers of transcription factors and that no single transcription factor is both necessary and sufficient to drive the differentiation process.

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Acknowledgements

We thank A. Ambesi, H. Atsui, M. Bansal, V. Belcastro, H. Daub, D. di Bernardo, M. Furuya, A. Hasegawa, K. Hayashida, A. Hirakiyama, F. Hori, K. Koseki, S. Kuhara, N. Miyamoto, S. Miyano, M. Nishikawa, C. Ohinata, M. Persson, S. Saihara, C. Sakaba, H. Sano, E. Shibazaki, T. Takagi, K. Toyoda, Y. Tsujimura and M. Yamamoto for discussion, encouragement and technical assistance. We thank M. Muramatsu, T. Ogawa, Y. Sakaki and A. Wada for support and encouragement. This work was mainly supported by grants for the Genome Network Project from the Ministry of Education, Culture, Sports, Science and Technology, Japan (Y.H.), Research Grant for the RIKEN Genome Exploration Research Project from the Ministry of Education, Culture, Sports, Science and Technology of the Japanese Government (Y.H.) and the RIKEN Frontier Research System, Functional RNA research program (Y.H.). A.R.R.F. is supported by a CJ Martin Fellowship from the Australian National Health and Medical Research Council (ID 428261). E.v.N. acknowledges support from SNF grant SNF #3100A0-118318.

Author information

Author notes

    • Harukazu Suzuki
    • , Alistair R R Forrest
    •  & Erik van Nimwegen

    These authors contributed equally to this work.

    • Harukazu Suzuki
    • , Alistair R R Forrest
    • , Erik van Nimwegen
    • , Carsten O Daub
    • , Piotr J Balwierz
    • , Katharine M Irvine
    • , Timo Lassmann
    • , Timothy Ravasi
    • , Yuki Hasegawa
    • , Michiel J L de Hoon
    • , Shintaro Katayama
    • , Kate Schroder
    • , Piero Carninci
    • , Yasuhiro Tomaru
    • , Mutsumi Kanamori-Katayama
    • , Atsutaka Kubosaki
    • , Vladimir B Bajic
    • , Takashi Gojobori
    • , Sean M Grimmond
    • , Winston Hide
    • , Boris Lenhard
    • , John Quackenbush
    • , Jesper Tegnér
    • , Christine A Wells
    • , David A Hume
    • , Jun Kawai
    •  & Yoshihide Hayashizaki

    These authors are the core writing group.

    • Harukazu Suzuki
    • , Alistair R R Forrest
    • , Erik van Nimwegen
    • , Carsten O Daub
    • , Katharine M Irvine
    • , Timo Lassmann
    • , Timothy Ravasi
    • , Kate Schroder
    • , David A Hume
    •  & Yoshihide Hayashizaki

    These authors are affiliated with the FANTOM 4 headquarters.

Affiliations

  1. RIKEN Omics Science Center, RIKEN Yokohama Institute, Kanagawa, Japan.

    • Harukazu Suzuki
    • , Alistair R R Forrest
    • , Carsten O Daub
    • , Timo Lassmann
    • , Yuki Hasegawa
    • , Michiel J L de Hoon
    • , Shintaro Katayama
    • , Piero Carninci
    • , Yasuhiro Tomaru
    • , Mutsumi Kanamori-Katayama
    • , Atsutaka Kubosaki
    • , Yoshinari Ando
    • , Erik Arner
    • , Nicolas Bertin
    • , Erika Bulger
    • , Masaaki Furuno
    • , Takehiro Hashimoto
    • , Ryoko Ishihara
    • , Hideya Kawaji
    • , Yasumasa Kimura
    • , Shinji Kondo
    • , Andreas Lennartsson
    • , Marina Lizio
    • , Norihiro Maeda
    • , Mika Nakano
    • , Haruka Okuda-Yabukami
    • , Charles Plessy
    • , Jessica Severin
    • , Masanori Suzuki
    • , Takahiro Suzuki
    • , Kazunori Waki
    • , Andrew Waterhouse
    • , Kazumi Yamaguchi
    • , Jun Yasuda
    • , Takahiro Arakawa
    • , Shiro Fukuda
    • , Kengo Imamura
    • , Chikatoshi Kai
    • , Ai Kaiho
    • , Tsugumi Kawashima
    • , Chika Kawazu
    • , Yayoi Kitazume
    • , Miki Kojima
    • , Hisashi Miura
    • , Kayoko Murakami
    • , Mitsuyoshi Murata
    • , Noriko Ninomiya
    • , Hiromi Nishiyori
    • , Shohei Noma
    • , Chihiro Ogawa
    • , Takuma Sano
    • , Christophe Simon
    • , Michihira Tagami
    • , Yukari Takahashi
    • , Jun Kawai
    •  & Yoshihide Hayashizaki
  2. The Eskitis Institute for Cell and Molecular Therapies, Griffith University, Australia.

    • Alistair R R Forrest
    • , Anthony G Beckhouse
    • , Alistair M Chalk
    • , Nicholas A Matigian
    •  & Christine A Wells
  3. Biozentrum, University of Basel, and Swiss Institute of Bioinformatics, Basel, Switzerland.

    • Erik van Nimwegen
    • , Piotr J Balwierz
    • , Mikhail Pachkov
    •  & Mihaela Zavolan
  4. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.

    • Katharine M Irvine
    • , Kate Schroder
    • , Timothy Bailey
    •  & Denis Bauer
  5. Department of Bioengineering, Jacobs School of Engineering, University of California, San Diego, La Jolla, California, USA.

    • Timothy Ravasi
    • , Ariel S Schwartz
    •  & Kai Tan
  6. Bergen Center for Computational Science, Bergen, Norway.

    • Altuna Akalin
    • , Pär G Engström
    • , David Fredman
    •  & Boris Lenhard
  7. National Research Institute for Child Health and Development, Tokyo, Japan.

    • Maki Asada
    • , Hiroshi Asahara
    •  & Megumi Hashimoto
  8. South African National Bioinformatics Institute, University of the Western Cape, Bellville, South Africa.

    • Vladimir B Bajic
    • , Adam Dawe
    • , Magbubah Essack
    • , Winston Hide
    • , Oliver Hofmann
    • , Mandeep Kaur
    • , Adele Kruger
    • , Cameron MacPherson
    • , Christopher A Maher
    • , Monique Maqungo
    • , Stuart Meier
    • , Aleksandar Radovanovic
    •  & Sebastian Schmeier
  9. Computational Medicine Group, Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.

    • Johan Björkegren
    •  & Jesper Tegnér
  10. Institute of Infectious Disease and Molecular Medicine (IIDMM), Wolfson Pavilion Level 2, Faculty of Health Sciences, University of Cape Town, Observatory, South Africa.

    • Frank Brombacher
  11. Department of Biological Science and Technology, Tokyo University of Science, Japan.

    • Joe Chiba
    • , Ryuichiro Kimura
    •  & Kazuhiko Nakabayashi
  12. Australian Research Council (ARC) Special Research Centre for Functional and Applied Genomics, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Australia.

    • Nicole Cloonan
    • , Geoffrey J Faulkner
    • , Sean M Grimmond
    • , John S Mattick
    • , Cas Simons
    •  & Ryan J Taft
  13. Department of Biochemistry, McGill University, Montreal, Quebec, Canada.

    • Josee Dostie
  14. Australian Research Council (ARC) Centre of Excellence in Bioinformatics, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Australia.

    • J Lynn Fink
    • , Markus C Kerr
    •  & Rohan D Teasdale
  15. Laboratory of Biodefense and Regulation, Osaka University of Pharmaceutical Sciences, Osaka, Japan.

    • Ko Fujimori
  16. Research Organization of Information and Systems, Center for Information Biology and DNA Data Bank of Japan (DDBJ), National Institute of Genetics, Shizuoka, Japan.

    • Takashi Gojobori
    • , Kazuho Ikeo
    • , Takeshi Konno
    • , Sei Miyamoto
    • , Toshitsugu Okayama
    •  & Miho Sera
  17. Department of Computer Science, University of Bristol, Merchant Venturers Building, Woodland Road, Bristol, UK.

    • Julian Gough
  18. Department of Science and Technology, Linköping University, Norrköping, Sweden.

    • Mika Gustafsson
    •  & Michael Hörnquist
  19. Computational and Experimental Systems Biology Group, RIKEN Genomic Sciences Center, RIKEN Yokohama Institute, Kanagawa Japan.

    • Mariko Hatakeyama
    •  & Toshio Kojima
  20. Department of Diabetes and Endcrinology, Flinders University and Medical Centre, Bedford Park, Adelaide, Australia.

    • Susanne Heinzel
    • , Nikolai Petrovsky
    •  & Linda Wu
  21. Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Winston Hide
    •  & Oliver Hofmann
  22. Department of Cell and Molecular Biology (CMB), Karolinska Institutet, Stockholm, Sweden.

    • Lukasz Huminiecki
  23. Cellular Dynamics Laboratory, Discovery and Research Institute, RIKEN Wako Institute, Saitama, Japan.

    • Naoko Imamoto
  24. Graduate School of Medicine and Faculty of Medicine, the University of Tokyo, Tokyo, Japan.

    • Satoshi Inoue
  25. Department of Biological and Chemical Engineering, Gunma University Faculty of Engineering, Gunma, Japan.

    • Yusuke Inoue
  26. R&D Solution Center, Research & Development Group, Hitachi Ltd., Tokyo, Japan.

    • Takao Iwayanagi
  27. The Bioinformatics Centre, Department of Biology and Biotech Research & Innovation Centre, University of Copenhagen, Copenhagen, Denmark.

    • Anders Jacobsen
    • , Anders Krogh
    • , Morten Lindow
    • , Sanne Nygaard
    • , Albin Sandelin
    • , Eivind Valen
    •  & Ole Winther
  28. Department of Information and Knowledge Engineering, Faculty of Engineering, Tottori University, Tottori, Japan.

    • Syuhei Kimura
  29. The Systems Biology Institute, Shibuya, Tokyo, Japan.

    • Hiroaki Kitano
  30. Department of Human Gene Research, Kazusa DNA Research Institute, Chiba, Japan.

    • Hisashi Koga
  31. Department of Biochemistry and Molecular Biology, the George Washington University Medical Center, Washington, D.C., USA.

    • Ajit Kumar
    •  & George St. Laurent
  32. Department of Biostatistics, Harvard School of Public Health, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Jessica Mar
    •  & John Quackenbush
  33. Department of Bioinformatic Engineering, Graduate School of Information Science and Technology, Osaka University, Osaka, Japan.

    • Hideo Matsuda
    •  & Yoichi Takenaka
  34. Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama, Japan.

    • Etsuko Miyamoto-Sato
    •  & Hiroshi Yanagawa
  35. Division of Functional Genomics and Systems Medicine, Research Center for Genomic Medicine, Saitama Medical School, Saitama, Japan.

    • Yutaka Nakachi
    •  & Yasushi Okazaki
  36. Dulbecco Telethon Institute, IRCCS Fondazione Santa Lucia at EBRI, Rome and IGB CNR, Naples, Italy.

    • Valerio Orlando
  37. Central Research Laboratory, Hitachi Ltd., Tokyo, Japan.

    • Jun Otomo
    •  & Shizu Takeda
  38. Department of Hematology and Oncology, University of Regensburg, Hospital, Regensburg, Germany.

    • Michael Rehli
  39. Faculty of Environment and Information Studies, Keio University, Fujisawa, Kanagawa, Japan.

    • Rintaro Saito
  40. School of Biological Science, Division of Genomics and Genetics, Nanyang Technological University, Singapore.

    • Christian Schönbach
  41. MRC Human Genetics Unit, Western, General Hospital, Crewe Road, Edinburgh, UK.

    • Colin A Semple
  42. Department of Computer Science, Graduate School of Information Science and Engineering, Tokyo Institute of Technology, Tokyo, Japan.

    • Katsuhiko Shirahige
  43. Institute for Molecular Bioscience, School of Molecular and Microbial Sciences, CRC for Chronic Inflammatory Diseases, The University of Queensland, St. Lucia, Australia.

    • Matthew J Sweet
  44. EMBL European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

    • Martin S Taylor
  45. Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden.

    • Jesper Tegnér
  46. Structural Studies Division MRC Laboratory of Molecular Biology, Hills Rd., Cambridge, UK.

    • Sarah Teichmann
  47. Biochemistry/Neuroscience, the Scripps Research Institute, Jupiter, Florida, USA.

    • Claes Wahlestedt
  48. The Roslin Institute and Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Roslin, UK.

    • David A Hume

Consortia

  1. The FANTOM Consortium

    A full list of authors and affiliations is provided at the end of this paper.

  2. Riken Omics Science Center

    A full list of authors and affiliations is provided at the end of this paper.

Authors

    Contributions

    A.A., A.M.C., A.D., A. Kruger, A. Krogh, A.R., A.R.R.F., A.S., A.S.S., A.W., B.L., C.A.M., C.A.S., C.A.W., C.O.D., C.M., C. Simons, C. Schönbach, C.W., D.B., E.A., E.V., E.v.N., G.J.F., H. Kawaji, H. Kitano, H. Matsuda, J.L.F., J.G., J.M., J.Q., J.S., J.S.M., J.T., K. Ikeo, K.T., K.W., K.Y., L.H., M.d.H., M.E., M.G., M. Hörnquist, M. Kaur, M. Lizio, M. Maqungo, M.P., M. Sera, M.S.T., M.T., M.Z., N.B., N.C., O.H., O.W., P.J.B., P.G.E., R.I., R.J.T., R.S., R.D.T., S.F., S. Kondo, S. Katayama, S. Kimura, S. Meier, S.S., S. Teichmann, T.B., T.G., T.H., T.I., T. Konno, T.L., T.O., T.R., V.B.B., W.H., Y. Kimura, Y.N. and Y. Takenaka were involved in bioinformatic aspects of the project. A.G.B., A.J., A. Kaiho, A. Kubosaki, A. Kumar, A.L., A.R.R.F., C.A.W., C. Kai, C. Kawazu, C.O., C.P., C. Simon, C.W., D.A.H., E.B., E.M.-S., F.B., G.S.L., H. Koga, H. Miura, H.N., H.O.-Y., H.S., H.Y., J.B., J.C., J.K., J.O., J.S.M., J.Y., K.F., K. Imamura, K.M., K.M.I., K.N., K. Schroder, K. Shirahige, L.W., M.A., M.C.K., M.F., M. Hashimoto, M. Hatakeyama, M.J.S., M.K.-K., M. Kojima, M. Murata, M.N., M.R., M. Suzuki, M.T., N.A.M., N.I., N.N., N.P., R.K., R.D.T., S.M.G., S.H., S.I., S. Miyamoto, S. Noma, S. Nygaard, S. Takeda, T.A., T. Kawashima, T. Kojima, T. Sano, T. Suzuki, V.O., Y.A., Y. Hasegawa, Y.I., Y. Kitazume, Y.N., Y.O., Y. Takahashi and Y. Tomaru were involved in biological aspects of the project. A.M.C., A.R.R.F., A.S., B.L., C.O.D., D.F., E.A., E.v.N., G.J.F., H.A., H.S., J.D., J.M., J.Q., J.S.M., K.W., M. Lindow, M.Z., N.C., N.M., O.H., P.J.B., P.C., R.J.T., R.S., S.M.G., S. Kondo, T.L., T.R. and V.O. were involved in the genome-wide and RNA analyses. E.v.N. and P.J.B. designed and carried out the motif activity response analysis. A.R.R.F., E.v.N., Y. Tomaru and M.K.-K. carried out the siRNA analysis. A.R.R.F., C.O.D., D.A.H., E.v.N., H.S., J.K., P.C. and Y. Hayashizaki oversaw the project. H.S., A.R.R.F., E.v.N., and D.A.H. wrote the manuscript with assistance from T.R., T.L., M.J.S., Y. Hasegawa, M.d.H., K.M.I., K.Schloder, P.J.C., P.J.B., E.A., N.P., M.R., S.M.G., C.A.W., J.Q., W.H., A. Kubosaki, Y. Tomaru, V.B.B., M. Suzuki and Y. Hayashizaki.

    Corresponding authors

    Correspondence to David A Hume or Yoshihide Hayashizaki.

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    DOI

    https://doi.org/10.1038/ng.375

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