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The Pu.1 target gene Zbtb11 regulates neutrophil development through its integrase-like HHCC zinc finger

Author

Listed:
  • Maria-Cristina Keightley

    (Australian Regenerative Medicine Institute, Monash University
    The Walter and Eliza Hall Institute of Medical Research)

  • Duncan P. Carradice

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Judith E. Layton

    (The Walter and Eliza Hall Institute of Medical Research
    Ludwig Institute for Cancer Research, Melbourne-Parkville Branch, The Royal Melbourne Hospital)

  • Luke Pase

    (Australian Regenerative Medicine Institute, Monash University
    The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Julien Y. Bertrand

    (University of Geneva—CMU)

  • Johannes G. Wittig

    (Australian Regenerative Medicine Institute, Monash University)

  • Aleksandar Dakic

    (The Walter and Eliza Hall Institute of Medical Research)

  • Andrew P. Badrock

    (Faculty of Life Sciences, The University of Manchester)

  • Nicholas J. Cole

    (Motor Neuron Disease Research Group, Faculty of Medicine and Health Sciences, Macquarie University)

  • David Traver

    (University of California at San Diego)

  • Stephen L. Nutt

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Julia McCoey

    (Monash University)

  • Ashley M. Buckle

    (Monash University)

  • Joan K. Heath

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne
    Ludwig Institute for Cancer Research, Melbourne-Parkville Branch, The Royal Melbourne Hospital)

  • Graham J. Lieschke

    (Australian Regenerative Medicine Institute, Monash University
    The Walter and Eliza Hall Institute of Medical Research
    Ludwig Institute for Cancer Research, Melbourne-Parkville Branch, The Royal Melbourne Hospital)

Abstract

In response to infection and injury, the neutrophil population rapidly expands and then quickly re-establishes the basal state when inflammation resolves. The exact pathways governing neutrophil/macrophage lineage outputs from a common granulocyte-macrophage progenitor are still not completely understood. From a forward genetic screen in zebrafish, we identify the transcriptional repressor, ZBTB11, as critical for basal and emergency granulopoiesis. ZBTB11 sits in a pathway directly downstream of master myeloid regulators including PU.1, and TP53 is one direct ZBTB11 transcriptional target. TP53 repression is dependent on ZBTB11 cys116, which is a functionally critical, metal ion-coordinating residue within a novel viral integrase-like zinc finger domain. To our knowledge, this is the first description of a function for this domain in a cellular protein. We demonstrate that the PU.1–ZBTB11–TP53 pathway is conserved from fish to mammals. Finally, Zbtb11 mutant rescue experiments point to a ZBTB11-regulated TP53 requirement in development of other organs.

Suggested Citation

  • Maria-Cristina Keightley & Duncan P. Carradice & Judith E. Layton & Luke Pase & Julien Y. Bertrand & Johannes G. Wittig & Aleksandar Dakic & Andrew P. Badrock & Nicholas J. Cole & David Traver & Steph, 2017. "The Pu.1 target gene Zbtb11 regulates neutrophil development through its integrase-like HHCC zinc finger," Nature Communications, Nature, vol. 8(1), pages 1-13, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14911
    DOI: 10.1038/ncomms14911
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