The Pu.1 target gene Zbtb11 regulates neutrophil development through its integrase-like HHCC zinc finger
Web of Science
AuthorKeightley, M-C; Carradice, DP; Layton, JE; Pase, L; Bertrand, JY; Wittig, JG; Dakic, A; Badrock, AP; Cole, NJ; Traver, D; ...
Source TitleNature Communications
PublisherNATURE PUBLISHING GROUP
University of Melbourne Author/sCarradice, Duncan; Nutt, Stephen; Dakic, Aleksandar; Heath, Joan; PASE, LUKE
AffiliationMedical Biology (W.E.H.I.)
School of Mathematics and Statistics
Medicine and Radiology
Document TypeJournal Article
CitationsKeightley, 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 StatusOpen Access
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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