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

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    Author
    Keightley, M-C; Carradice, DP; Layton, JE; Pase, L; Bertrand, JY; Wittig, JG; Dakic, A; Badrock, AP; Cole, NJ; Traver, D; ...
    Date
    2017-04-06
    Source Title
    Nature Communications
    Publisher
    NATURE PUBLISHING GROUP
    University of Melbourne Author/s
    Carradice, Duncan; Nutt, Stephen; Dakic, Aleksandar; Heath, Joan; PASE, LUKE
    Affiliation
    Medical Biology (W.E.H.I.)
    School of Mathematics and Statistics
    Surgery (RMH)
    Medicine and Radiology
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    Document Type
    Journal Article
    Citations
    Keightley, M. -C., Carradice, D. P., Layton, J. E., Pase, L., Bertrand, J. Y., Wittig, J. G., Dakic, A., Badrock, A. P., Cole, N. J., Traver, D., Nutt, S. L., McCoey, J., Buckle, A. M., Heath, J. K. & Lieschke, G. J. (2017). The Pu.1 target gene Zbtb11 regulates neutrophil development through its integrase-like HHCC zinc finger. NATURE COMMUNICATIONS, 8 (1), https://doi.org/10.1038/ncomms14911.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/259035
    DOI
    10.1038/ncomms14911
    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.

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