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

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, Stephen L. Nutt, Julia McCoey, Ashley M. Buckle, Joan K. Heath and Graham J. Lieschke ()
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Maria-Cristina Keightley: Australian Regenerative Medicine Institute, Monash University
Duncan P. Carradice: The Walter and Eliza Hall Institute of Medical Research
Judith E. Layton: The Walter and Eliza Hall Institute of Medical Research
Luke Pase: Australian Regenerative Medicine Institute, Monash University
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
Julia McCoey: Monash University
Ashley M. Buckle: Monash University
Joan K. Heath: The Walter and Eliza Hall Institute of Medical Research
Graham J. Lieschke: Australian Regenerative Medicine Institute, Monash University

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14911

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