1. Computational and Systems Biology
  2. Chromosomes and Gene Expression
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An experimentally validated network of nine haematopoietic transcription factors reveals mechanisms of cell state stability

  1. Judith Schütte
  2. Huange Wang
  3. Stella Antoniou
  4. Andrew Jarratt
  5. Nicola K Wilson
  6. Joey Riepsaame
  7. Fernando J Calero-Nieto
  8. Victoria Moignard
  9. Silvia Basilico
  10. Sarah J Kinston
  11. Rebecca L Hannah
  12. Mun Chiang Chan
  13. Sylvia T Nürnberg
  14. Willem H Ouwehand
  15. Nicola Bonzanni
  16. Marella FTR de Bruijn
  17. Berthold Göttgens  Is a corresponding author
  1. University Hospital Essen, Germany
  2. University of Cambridge, United Kingdom
  3. University of Oxford, United Kingdom
  4. Walter and Eliza Hall Institute of Medical Research, Australia
  5. University of Pennsylvania, United States
  6. VU University Amsterdam, Netherlands
Research Article
  • Cited 31
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Cite this article as: eLife 2016;5:e11469 doi: 10.7554/eLife.11469

Abstract

Transcription factor (TF) networks determine cell type identity by establishing and maintaining lineage-specific expression profiles, yet reconstruction of mammalian regulatory network models has been hampered by a lack of comprehensive functional validation of regulatory interactions. Here, we report comprehensive ChIP-Seq, transgenic and reporter gene experimental data that have allowed us to construct an experimentally validated regulatory network model for haematopoietic stem/progenitor cells (HSPCs). Model simulation coupled with subsequent experimental validation using single cell expression profiling revealed potential mechanisms for cell state stabilisation, and also how a leukemogenic TF fusion protein perturbs key HSPC regulators. The approach presented here should help to improve our understanding of both normal physiological and disease processes.

Article and author information

Author details

  1. Judith Schütte

    Department of Haematology, University Hospital Essen, Essen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Huange Wang

    Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Stella Antoniou

    MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Andrew Jarratt

    Division of Molecular Medicine, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
    Competing interests
    The authors declare that no competing interests exist.
  5. Nicola K Wilson

    Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Joey Riepsaame

    MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Fernando J Calero-Nieto

    Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Victoria Moignard

    Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Silvia Basilico

    Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Sarah J Kinston

    Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Rebecca L Hannah

    Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Mun Chiang Chan

    MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Sylvia T Nürnberg

    Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Willem H Ouwehand

    Department of Haematology, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  15. Nicola Bonzanni

    IBIVU Centre for Integrative Bioinformatics, VU University Amsterdam, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  16. Marella FTR de Bruijn

    MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  17. Berthold Göttgens

    Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
    For correspondence
    bg200@cam.ac.uk
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: All mice were housed in microisolator cages and provided continuously with sterile food, water, and bedding. All mice were kept in specified pathogen-free conditions, and all procedures were performed according to the United Kingdom Home Office regulations under project licence 70/8406

Reviewing Editor

  1. Amy J Wagers, Harvard University, United States

Publication history

  1. Received: September 9, 2015
  2. Accepted: February 12, 2016
  3. Accepted Manuscript published: February 22, 2016 (version 1)
  4. Version of Record published: March 10, 2016 (version 2)

Copyright

© 2016, Schütte et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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