PUBLICATION

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

Authors
Keightley, M.C., Carradice, D.P., Layton, J.E., Pase, L., Bertrand, J.Y., Wittig, J.G., Dakic, A., Badrock, A.P., Cole, N.J., Traver, D., Nutt, S.L., McCoey, J., Buckle, A.M., Heath, J.K., Lieschke, G.J.
ID
ZDB-PUB-170407-2
Date
2017
Source
Nature communications   8: 14911 (Journal)
Registered Authors
Badrock, Andrew P., Bertrand, Julien, Carradice, Duncan, Cole, Nicholas, Heath, Joan K., Keightley, M. Cristina, Layton, Judy E., Lieschke, Graham J., Pase, Luke, Traver, David, Wittig, Johannes
Keywords
Development, Gene regulation, Myelopoiesis, Transcription factors
Datasets
GEO:GSE94532, GEO:GSE239949
MeSH Terms
  • Leukopoiesis/genetics*
  • Animals
  • Animals, Genetically Modified
  • Trans-Activators/metabolism*
  • Zebrafish
  • Tumor Suppressor Protein p53/metabolism*
  • Zebrafish Proteins/genetics*
  • Zinc Fingers
  • Proto-Oncogene Proteins/metabolism*
  • Neutrophils*
  • Repressor Proteins/genetics*
  • Databases, Protein
  • Signal Transduction
(all 13)
PubMed
28382966 Full text @ Nat. Commun.
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.
Genes / Markers
Figures
Figure Gallery (9 images)
Show all Figures
Expression
Phenotype
Fish Conditions Stage Phenotype Figure
tp53zdf1/zdf1; zbtb11gl11/gl11; mq8TgcontrolLong-pec
zbtb11gl11/gl11controlLong-pec
zbtb11gl11/gl11controlLong-pec
zbtb11gl11/gl11controlLong-pec
zbtb11gl11/gl11controlLong-pec
zbtb11gl11/gl11controlLong-pec
zbtb11gl11/gl11controlLong-pec
zbtb11gl11/gl11controlLong-pec
zbtb11gl11/gl11controlLong-pec
zbtb11gl11/gl11controlProtruding-mouth
1 - 10 of 26
Show
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
c264TgTransgenic Insertion
    gl11
      		Point Mutation
      gl12
        		Complex
        gl24TgTransgenic Insertion
          gl26TgTransgenic Insertion
            i114TgTransgenic Insertion
              mq8TgTransgenic Insertion
                nz50TgTransgenic Insertion
                  sd2TgTransgenic Insertion
                    zdf1
                      		Point Mutation
                      1 - 10 of 10
                      Show
                      Human Disease / Model
                      No data available
                      Sequence Targeting Reagents
                      Target Reagent Reagent Type
                      tp53MO4-tp53MRPHLNO
                      zbtb11CRISPR1-zbtb11CRISPR
                      zbtb11MO1-zbtb11MRPHLNO
                      1 - 3 of 3
                      Show
                      Fish
                      Fish
                      c264Tg; gl24Tg; i114Tg
                      c264Tg; gl24Tg; i114Tg + MO1-zbtb11
                      i114Tg
                      sd2Tg
                      tp53zdf1/zdf1; zbtb11gl11/gl11; mq8Tg
                      WT
                      zbtb11gl11/gl11
                      zbtb11gl11/gl11; gl26Tg
                      zbtb11gl11/gl11; i114Tg
                      zbtb11gl11/gl11; mq8Tg
                      1 - 10 of 14
                      Show
                      Antibodies
                      No data available
                      Orthology
                      No data available
                      Engineered Foreign Genes
                      Marker Marker Type Name
                      DsRedEFGDsRed
                      DsRed2EFGDsRed2
                      GAL4EFGGAL4
                      GFPEFGGFP
                      mCherryEFGmCherry
                      NTREFGNTR
                      VenusEFGVenus
                      1 - 7 of 7
                      Show
                      Mapping
                      No data available
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                      Citation
                      Keightley, M.C., Carradice, D.P., Layton, J.E., Pase, L., Bertrand, J.Y., Wittig, J.G., Dakic, A., Badrock, A.P., Cole, N.J., Traver, D., Nutt, S.L., McCoey, J., Buckle, A.M., Heath, J.K., Lieschke, G.J. (2017) The Pu.1 target gene Zbtb11 regulates neutrophil development through its integrase-like HHCC zinc finger. Nature communications. 8:14911.