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

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.

authors

  • Keightley, Maria Cristina
  • Carradice, Duncan P
  • Layton, Judith E
  • Pase, Luke
  • Bertrand, Julien Y
  • Wittig, Johannes G
  • Dakic, Aleksandar
  • Badrock, Andrew P
  • Cole, Nicholas J
  • Traver, David
  • Nutt, Stephen L
  • McCoey, Julia
  • Buckle, Ashley M
  • Heath, Joan K
  • Lieschke, Graham J

publication date

  • 2017