Article abstract


Nature Genetics 41, 553 - 562 (2009)
Published online: 19 April 2009 | doi:10.1038/ng.375

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

The FANTOM Consortium & Riken Omics Science Center1


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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  1. A full list of authors and affiliations is provided at the end of this paper.
  2. RIKEN Omics Science Center, RIKEN Yokohama Institute, Kanagawa, Japan.
  3. The Eskitis Institute for Cell and Molecular Therapies, Griffith University, Australia.
  4. Biozentrum, University of Basel, and Swiss Institute of Bioinformatics, Basel, Switzerland.
  5. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
  6. Department of Bioengineering, Jacobs School of Engineering, University of California, San Diego, La Jolla, California, USA.
  7. Bergen Center for Computational Science, Bergen, Norway.
  8. National Research Institute for Child Health and Development, Tokyo, Japan.
  9. South African National Bioinformatics Institute, University of the Western Cape, Bellville, South Africa.
  10. Computational Medicine Group, Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
  11. Institute of Infectious Disease and Molecular Medicine (IIDMM), Wolfson Pavilion Level 2, Faculty of Health Sciences, University of Cape Town, Observatory, South Africa.
  12. Department of Biological Science and Technology, Tokyo University of Science, Japan.
  13. Australian Research Council (ARC) Special Research Centre for Functional and Applied Genomics, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Australia.
  14. Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
  15. Australian Research Council (ARC) Centre of Excellence in Bioinformatics, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Australia.
  16. Laboratory of Biodefense and Regulation, Osaka University of Pharmaceutical Sciences, Osaka, Japan.
  17. Research Organization of Information and Systems, Center for Information Biology and DNA Data Bank of Japan (DDBJ), National Institute of Genetics, Shizuoka, Japan.
  18. Department of Computer Science, University of Bristol, Merchant Venturers Building, Woodland Road, Bristol, UK.
  19. Department of Science and Technology, Linköping University, Norrköping, Sweden.
  20. Computational and Experimental Systems Biology Group, RIKEN Genomic Sciences Center, RIKEN Yokohama Institute, Kanagawa Japan.
  21. Department of Diabetes and Endcrinology, Flinders University and Medical Centre, Bedford Park, Adelaide, Australia.
  22. Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.
  23. Department of Cell and Molecular Biology (CMB), Karolinska Institutet, Stockholm, Sweden.
  24. Cellular Dynamics Laboratory, Discovery and Research Institute, RIKEN Wako Institute, Saitama, Japan.
  25. Graduate School of Medicine and Faculty of Medicine, the University of Tokyo, Tokyo, Japan.
  26. Department of Biological and Chemical Engineering, Gunma University Faculty of Engineering, Gunma, Japan.
  27. R&D Solution Center, Research & Development Group, Hitachi Ltd., Tokyo, Japan.
  28. The Bioinformatics Centre, Department of Biology and Biotech Research & Innovation Centre, University of Copenhagen, Copenhagen, Denmark.
  29. Department of Information and Knowledge Engineering, Faculty of Engineering, Tottori University, Tottori, Japan.
  30. The Systems Biology Institute, Shibuya, Tokyo, Japan.
  31. Department of Human Gene Research, Kazusa DNA Research Institute, Chiba, Japan.
  32. Department of Biochemistry and Molecular Biology, the George Washington University Medical Center, Washington, D.C., USA.
  33. Department of Biostatistics, Harvard School of Public Health, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  34. Department of Bioinformatic Engineering, Graduate School of Information Science and Technology, Osaka University, Osaka, Japan.
  35. Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama, Japan.
  36. Division of Functional Genomics and Systems Medicine, Research Center for Genomic Medicine, Saitama Medical School, Saitama, Japan.
  37. Dulbecco Telethon Institute, IRCCS Fondazione Santa Lucia at EBRI, Rome and IGB CNR, Naples, Italy.
  38. Central Research Laboratory, Hitachi Ltd., Tokyo, Japan.
  39. Department of Hematology and Oncology, University of Regensburg, Hospital, Regensburg, Germany.
  40. Faculty of Environment and Information Studies, Keio University, Fujisawa, Kanagawa, Japan.
  41. School of Biological Science, Division of Genomics and Genetics, Nanyang Technological University, Singapore.
  42. MRC Human Genetics Unit, Western, General Hospital, Crewe Road, Edinburgh, UK.
  43. Department of Computer Science, Graduate School of Information Science and Engineering, Tokyo Institute of Technology, Tokyo, Japan.
  44. Institute for Molecular Bioscience, School of Molecular and Microbial Sciences, CRC for Chronic Inflammatory Diseases, The University of Queensland, St. Lucia, Australia.
  45. EMBL European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
  46. Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden.
  47. Structural Studies Division MRC Laboratory of Molecular Biology, Hills Rd., Cambridge, UK.
  48. Biochemistry/Neuroscience, the Scripps Research Institute, Jupiter, Florida, USA.
  49. The Roslin Institute and Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Roslin, UK.
  50. These authors contributed equally to this work.
  51. These authors are the core writing group.
  52. These authors are affiliated with the FANTOM 4 headquarters.

Correspondence to: e-mail: david.hume@roslin.ed.ac.uk

Correspondence to: e-mail: yosihide@gsc.riken.jp