Oral Annual Conference of the Genetics Society of Australasia with the NZ Society for Biochemistry & Molecular Biology

Zbtb11 regulates TP53 and is required for definitive haemopoiesis (743)

Maria-Cristina Keightley 1 , Joly Kwek 1 , Graham J Lieschke 1
  1. Australian Regenerative Medicine Institute, Clayton, VIC, Australia

Haemopoiesis caters to the daily demands of producing and maintaining the various blood cell lineages in the right quantities. In response to injury and infection it must rapidly generate vast numbers of specific lineages. It is important to understand the sophisticated mechanisms regulating this balancing act so that therapeutic targets manipulating blood cell production can be developed for disease treatment. ZBTB11 is a ZBTB (BTB/POZ) transcription factor we have shown is required for early myeloid development and subsequently for maintenance of haemopoietic stem cells in the zebrafish zbtb11 mutant mne. Depletion of other cell lineages at later time points supports a broad failure of definitive haemopoiesis in Zbtb11 deficiency. Master myeloid regulators Pu.1, C/ebpα and Gfi1 regulate both zebrafish and human ZBTB11 luciferase reporters cementing a conserved place for ZBTB11 in the haemopoietic transcription factor hierarchy. Tp53 is upregulated in mne neutrophils and is a direct target of ZBTB11 in luciferase assays in human 293-HEK cells. RNAseq profiling of neutrophils identified apoptosis and cell proliferation as Zbtb11 target gene networks. Evaluation of cell death and proliferation show increased apoptosis in mne consistent with the location of proliferative cells in WT. At 48hpf, however, there is no detectable overlap between apoptotic cells and neutrophils. EdU incorporation is strikingly absent throughout mne, and is p53-independent, pointing to cell cycle arrest as a potential contributor to Zbtb11-compromised haemopoietic depletion. Together these data demonstrate a critical role for Zbtb11 in zebrafish haemopoiesis and identify Zbtb11-centered pathways that are conserved from zebrafish to mammals.