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

doi:10.1038/ncomms14911

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^*

^*Corresponding author for this work

Division of Evolution, Infection and Genomics

Research output: Contribution to journal › Article › peer-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 language	English
Article number	14911
Journal	Nature Communications
Volume	8
Early online date	6 Apr 2017
DOIs	https://doi.org/10.1038/ncomms14911
Publication status	Published - 2017

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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, Article 14911. https://doi.org/10.1038/ncomms14911

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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.",

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

year = "2017",

doi = "10.1038/ncomms14911",

language = "English",

volume = "8",

journal = "Nature Communications",

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T1 - The Pu.1 target gene Zbtb11 regulates neutrophil development through its integrase-like HHCC zinc finger

AU - Keightley, Maria Cristina

AU - Carradice, Duncan P.

AU - Layton, Judith E.

AU - Pase, Luke

AU - Bertrand, Julien Y.

AU - Wittig, Johannes G.

AU - Dakic, Aleksandar

AU - Badrock, Andrew P.

AU - Cole, Nicholas J.

AU - Traver, David

AU - Nutt, Stephen L.

AU - McCoey, Julia

AU - Buckle, Ashley M.

AU - Heath, Joan K.

AU - Lieschke, Graham J.

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

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VL - 8

JO - Nature Communications

JF - Nature Communications

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

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