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, Graham J. Lieschke

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number14911
JournalNature Communications
Volume8
Early online date6 Apr 2017
DOIs
Publication statusPublished - 2017

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