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

Nature Genetics volume 41, pages 553–562 (2009)Cite this article

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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Figure 1: Motif Activity Response Analysis (MARA).
Figure 2: Statistical significance and consistency across replicates of the inferred motif activity profiles.
Figure 3: Inferred time-dependent activities of the key regulatory motifs.
Figure 4: Predicted core regulatory network of the 30 core motifs.
Figure 5: Validation of predicted target promoter sets using siRNA knockdowns.
Figure 6: Most significant motif activity changes (as measured by z value, red bars) for four TF gene knockdowns that induce motif activity changes that have a differentiative overlap with the PMA time course of more than 50%.

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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

  1. Harukazu Suzuki, Alistair R R Forrest, Erik van Nimwegen and David A Hume: These authors contributed equally to this work.

  2. 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 and Yoshihide Hayashizaki: These authors are the core writing group.

  3. Harukazu Suzuki, Alistair R R Forrest, Erik van Nimwegen, Carsten O Daub, Katharine M Irvine, Timo Lassmann, Timothy Ravasi, Kate Schroder, David A Hume and Yoshihide Hayashizaki: These authors are affiliated with the FANTOM 4 headquarters.

Authors and 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. Department of Medicine, Computational Medicine Group, Atherosclerosis Research Unit, Center for Molecular 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. Department of Biology and Biotech Research & Innovation Centre, The Bioinformatics 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. Division of Genomics and Genetics, School of Biological Science, 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

The FANTOM Consortium

  • 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
  • , Altuna Akalin
  • , Yoshinari Ando
  • , Erik Arner
  • , Maki Asada
  • , Hiroshi Asahara
  • , Timothy Bailey
  • , Vladimir B Bajic
  • , Denis Bauer
  • , Anthony G Beckhouse
  • , Nicolas Bertin
  • , Johan Björkegren
  • , Frank Brombacher
  • , Erika Bulger
  • , Alistair M Chalk
  • , Joe Chiba
  • , Nicole Cloonan
  • , Adam Dawe
  • , Josee Dostie
  • , Pär G Engström
  • , Magbubah Essack
  • , Geoffrey J Faulkner
  • , J Lynn Fink
  • , David Fredman
  • , Ko Fujimori
  • , Masaaki Furuno
  • , Takashi Gojobori
  • , Julian Gough
  • , Sean M Grimmond
  • , Mika Gustafsson
  • , Megumi Hashimoto
  • , Takehiro Hashimoto
  • , Mariko Hatakeyama
  • , Susanne Heinzel
  • , Winston Hide
  • , Oliver Hofmann
  • , Michael Hörnquist
  • , Lukasz Huminiecki
  • , Kazuho Ikeo
  • , Naoko Imamoto
  • , Satoshi Inoue
  • , Yusuke Inoue
  • , Ryoko Ishihara
  • , Takao Iwayanagi
  • , Anders Jacobsen
  • , Mandeep Kaur
  • , Hideya Kawaji
  • , Markus C Kerr
  • , Ryuichiro Kimura
  • , Syuhei Kimura
  • , Yasumasa Kimura
  • , Hiroaki Kitano
  • , Hisashi Koga
  • , Toshio Kojima
  • , Shinji Kondo
  • , Takeshi Konno
  • , Anders Krogh
  • , Adele Kruger
  • , Ajit Kumar
  • , Boris Lenhard
  • , Andreas Lennartsson
  • , Morten Lindow
  • , Marina Lizio
  • , Cameron MacPherson
  • , Norihiro Maeda
  • , Christopher A Maher
  • , Monique Maqungo
  • , Jessica Mar
  • , Nicholas A Matigian
  • , Hideo Matsuda
  • , John S Mattick
  • , Stuart Meier
  • , Sei Miyamoto
  • , Etsuko Miyamoto-Sato
  • , Kazuhiko Nakabayashi
  • , Yutaka Nakachi
  • , Mika Nakano
  • , Sanne Nygaard
  • , Toshitsugu Okayama
  • , Yasushi Okazaki
  • , Haruka Okuda-Yabukami
  • , Valerio Orlando
  • , Jun Otomo
  • , Mikhail Pachkov
  • , Nikolai Petrovsky
  • , Charles Plessy
  • , John Quackenbush
  • , Aleksandar Radovanovic
  • , Michael Rehli
  • , Rintaro Saito
  • , Albin Sandelin
  • , Sebastian Schmeier
  • , Christian Schönbach
  • , Ariel S Schwartz
  • , Colin A Semple
  • , Miho Sera
  • , Jessica Severin
  • , Katsuhiko Shirahige
  • , Cas Simons
  • , George St. Laurent
  • , Masanori Suzuki
  • , Takahiro Suzuki
  • , Matthew J Sweet
  • , Ryan J Taft
  • , Shizu Takeda
  • , Yoichi Takenaka
  • , Kai Tan
  • , Martin S Taylor
  • , Rohan D Teasdale
  • , Jesper Tegnér
  • , Sarah Teichmann
  • , Eivind Valen
  • , Claes Wahlestedt
  • , Kazunori Waki
  • , Andrew Waterhouse
  • , Christine A Wells
  • , Ole Winther
  • , Linda Wu
  • , Kazumi Yamaguchi
  • , Hiroshi Yanagawa
  • , Jun Yasuda
  • , Mihaela Zavolan
  •  & David A Hume

Riken Omics Science Center

  • 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

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

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

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Supplementary Methods, Supplementary Note, Supplementary Figures 1–17, Supplementary Tables 1–15 (PDF 4646 kb)

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The FANTOM Consortium., Riken Omics Science Center. The transcriptional network that controls growth arrest and differentiation in a human myeloid leukemia cell line. Nat Genet 41, 553–562 (2009). https://doi.org/10.1038/ng.375

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

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