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NORMAL HEMATOPOIESIS

Znf687 recruits Brd4-Smrt complex to regulate gfi1aa during neutrophil development

Leukemia volume 38, pages 851–864 (2024)Cite this article

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Abstract

Neutrophils are key component of the innate immune system in vertebrates. Diverse transcription factors and cofactors act in a well-coordinated manner to ensure proper neutrophil development. Dysregulation of the transcriptional program triggering neutrophil differentiation is associated with various human hematologic disorders such as neutropenia, neutrophilia, and leukemia. In the current study we show the zinc finger protein Znf687 is a lineage-preferential transcription factor, whose deficiency leads to an impaired neutrophil development in zebrafish. Mechanistically, Znf687 functions as a negative regulator of gfi1aa, a pivotal modulator in terminal granulopoiesis, to regulate neutrophil maturation. Moreover, we found BRD4, an important epigenetic regulator, directly interacts with ZNF687 in neutrophils. Deficiency of brd4 results in similar defective neutrophil development as observed in znf687 mutant zebrafish. Biochemical and genetic analyses further reveal that instead of serving as a canonical transcriptional coactivator, Brd4 directly interacts and bridges Znf687 and Smrt nuclear corepressor on gfi1aa gene’s promoter to exert transcription repression. In addition, the ZNF687-BRD4-SMRT-GFI1 transcriptional regulatory network is evolutionary conserved in higher vertebrate. Overall, our work indicates Znf687 and Brd4 are two novel master regulators in promoting terminal granulopoiesis.

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Fig. 1: Generation of two znf687 paralog-deficient zebrafish lines.
Fig. 2: Deficiency of znf687a specifically impairs neutrophil development in embryonic and adult zebrafish.
Fig. 3: Znf687 acts as a transcription repressor of gfi1aa in regulating neutrophil maturation.
Fig. 4: Brd4 orchestrates with Znf687 to repress gfi1aa expression during neutrophil development.
Fig. 5: Brd4 is recruited by Znf687 to the promoter region of gfi1aa.
Fig. 6: Brd4-Smrt corepressor complex mediates the transcriptional repression capacity of Znf687.
Fig. 7: A conserved role of ZNF687-BRD4-SMRT complex in mammalian neutrophils.

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Data availability

RNA sequencing dataset generated in this study has been deposited to Gene Expression Omnibus (GEO) database (GSE235609). These data are now available with an open access mandate.

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Acknowledgements

The authors are grateful to Dr. X Jiao (from the Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA) for his critical manuscript reading. This work was supported by research funding from the National Natural Science Foundation of China.

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Author notes

  1. These authors contributed equally: Lin Yan, Shuiyi Tan.

Authors and Affiliations

  1. Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Lin Yan, Shuiyi Tan, Haihong Wang, Hao Yuan, Xiaohui Liu, Yi Chen & Jun Zhou

  2. CNRS-LIA Hematology and Cancer, Sino-French Research Center for Life Sciences and Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Lin Yan, Shuiyi Tan, Haihong Wang, Hao Yuan, Xiaohui Liu, Hugues de Thé, Jun Zhu & Jun Zhou

  3. Université de Paris 7/INSERM/CNRS UMR 944/7212, Equipe Labellisée Ligue Nationale Contre le Cancer, Hôpital St. Louis, Paris, France

    Hugues de Thé & Jun Zhu

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Contributions

L.Y and S.T conducted most of the experiments and analyzed data. H.W conducted FACS analyses and cell sorting. H.Y and X.L performed RNA-seq, and conducted analysis of the RNA-seq data. Y.C maintained the zebrafish lines. H.d.T and J.Z provided advice regarding the experiments. J.Z designed the project, analyzed data, and wrote the manuscript.

Corresponding authors

Correspondence to Jun Zhu or Jun Zhou.

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The authors declare no competing interests.

Ethics

The study was approved by the Ethics Committee of Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine. Zebrafish experimental procedures were conducted in accordance with the protocols approved by the Institutional Animal Care and Use Committee (IACUC) of Shanghai Jiao Tong University (2020-3#).

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Yan, L., Tan, S., Wang, H. et al. Znf687 recruits Brd4-Smrt complex to regulate gfi1aa during neutrophil development. Leukemia 38, 851–864 (2024). https://doi.org/10.1038/s41375-024-02165-2

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