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Hematopoiesis
Interferon regulatory factor 2 binding protein 2b regulates neutrophil versus macrophage fate during zebrafish definitive myelopoiesis
Luxiang Wang,1* Shuo Gao,1* Haihong Wang,1* Chang Xue,1* Xiaohui Liu,1 Hao Yuan,1 Zixuan Wang,1 Saijuan Chen,1 Zhu Chen,1 Hugues de Thé,1,2 Yiyue Zhang,3 Wenqing Zhang,3 Jun Zhu1,2 and Jun Zhou1
1CNRS-LIA Hematology and Cancer, Sino-French Research Center for Life Sciences and Genomics, State Key Laboratory of Medical Genomics, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; 2Université de Paris 7/INSERM/CNRS UMR 944/7212, Equipe Labellisée No. 11 Ligue Nationale Contre le Cancer, Hôpital St. Louis, Paris, France and 3Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology, Guangzhou, China
*LW, SG, HW and CX contributed equally to this work.
ABSTRACT
Aproper choice of neutrophil-macrophage progenitor cell fate is essential for the generation of adequate myeloid subpopulations during embryonic development and in adulthood. The network gov- erning neutrophil-macrophage progenitor cell fate has several key determi- nants, such as myeloid master regulators CCAAT enhancer binding protein alpha (C/EBPα) and spleen focus forming virus proviral integration onco- gene (PU.1). Nevertheless, more regulators remain to be identified and char- acterized. To ensure balanced commitment of neutrophil-macrophage pro- genitors toward each lineage, the interplay among these determinants is not only synergistic, but also antagonistic. Depletion of interferon regulatory factor 2 binding protein 2b (Irf2bp2b), a well-known negative transcription regulator, results in a bias in neutrophil-macrophage progenitor cell fate in favor of macrophages at the expense of neutrophils during the stage of definitive myelopoiesis in zebrafish embryos. Mechanistic studies indicate that Irf2bp2b acts as a downstream target of C/EBPα, repressing PU.1 expression, and that SUMOylation confers the repressive function of Irf2bp2b. Thus, Irf2bp2b is a novel determinant in the choice of fate of neu- trophil-macrophage progenitor cells.
Introduction
Hematopoiesis is the process by which uncommitted hematopoietic stem cells proliferate and differentiate into all mature blood cell types.1 The stepwise devel- opment of multipotent hematopoietic stem cells undergoes sequential lineage potential limitations toward oligopotent and unipotent progenitor cells, eventually restricting their output.2 The molecular network governing every stage of hematopoiesis involves an interplay between multiple lineage-specific transcrip- tion factors/cofactors and epigenetic modifiers.3 Any tiny disturbance of these fac- tors could bias the lineage-restricted cell fate toward an alternate fate.4
Neutrophil-macrophage progenitors (NMP) generate neutrophil-macrophage lineage cells, mainly neutrophils, monocytes, and macrophages. The gene regula- tory network governing NMP cell fate is composed of primary determinants, CCAAT enhancer binding protein alpha (C/EBPα) and spleen focus forming virus proviral integration oncogene (PU.1), along with secondary determinants Gfi and Egr/Nab.5,6 Neutrophil cell fate specification requires C/EBPα, whereas macrophage cell fate specification depends on PU.1.7,8 The relative levels of C/EBPα and PU.1 determine the choice of NMP cell fate. A low C/EBPα:PU.1 ratio shifts the balance toward macrophage differentiation, whereas a high ratio directs granulocyte differentiation.6 To keep myeloid lineage fidelity, the interplay among
Ferrata Storti Foundation
Haematologica 2020 Volume 105(2):325-337
Correspondence:
JUN ZHOU
zj10802@rjh.com.cn
JUN ZHU
zhuj1966@yahoo.com or jun.zhu@paris7.jussieu.fr
WENQING ZHANG
mczhangwq@scut.edu.cn
Received: January 25, 2019. Accepted: May 20, 2019. Pre-published: May 23, 2019.
doi:10.3324/haematol.2019.217596
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/3/325
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