title: The Pu.1 target gene Zbtb11 regulates neutrophil development through its integrase-like HHCC zinc finger.
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.affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria 3800, Australia.|The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.
authors.forename: Maria-Cristina
authors.initials: MC
authors.lastname: Keightley
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Duncan P
authors.initials: DP
authors.lastname: Carradice
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.|Ludwig Institute for Cancer Research, Melbourne-Parkville Branch, The Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.
authors.forename: Judith E
authors.initials: JE
authors.lastname: Layton
authors.affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria 3800, Australia.|The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Luke
authors.initials: L
authors.lastname: Pase
authors.affiliation: Department of Pathology and Immunology, University of Geneva-CMU, 1211 Geneva 4, Switzerland.
authors.forename: Julien Y
authors.initials: JY
authors.lastname: Bertrand
authors.affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Johannes G
authors.identifier: 0000-0002-0598-2897
authors.initials: JG
authors.lastname: Wittig
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Dakic
authors.affiliation: Faculty of Life Sciences, The University of Manchester, Manchester M13 9PL, UK.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Badrock
authors.affiliation: Motor Neuron Disease Research Group, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Cole
authors.affiliation: Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California 92093, USA.
authors.forename: David
authors.initials: D
authors.lastname: Traver
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Nutt
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Julia
authors.initials: J
authors.lastname: McCoey
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Ashley M
authors.identifier: 0000-0003-2943-9044
authors.initials: AM
authors.lastname: Buckle
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.|Ludwig Institute for Cancer Research, Melbourne-Parkville Branch, The Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.
authors.forename: Joan K
authors.initials: JK
authors.lastname: Heath
authors.affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria 3800, Australia.|The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.|Ludwig Institute for Cancer Research, Melbourne-Parkville Branch, The Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.
authors.forename: Graham J
authors.identifier: 0000-0003-0325-798X
authors.initials: GJ
authors.lastname: Lieschke
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D030562:Databases, Protein; D019891:Leukopoiesis / Q000235:genetics*; D009504:Neutrophils; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics*; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics*; D016335:Zinc Fingers; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D029961:Zebrafish Proteins; D000099232:Proto-Oncogene Protein Spi-1; C000629165:Zbtb11 protein, zebrafish