Znf687 recruits Brd4-Smrt complex  to regulate gfi1aa expression   during neutrophil development
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-specific 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, 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. Overall, our work not only indicates Znf687 and Brd4 are reciprocally required in promoting granulopoiesis, but also provides new insights into the role of the two crucial regulators in transcriptional repression. Overall design: We found that Znf687 served as a transcription repressor.we speculated that the aberrant upregulation of certain downstream target of Znf687 would be responsible for the defective neutrophil differentiation. Then RNA sequencing (RNA-seq) analyses were conducted in the remaining mpx+ cells isolated from Tg(mpx:eGFP) and znf687a MO injected Tg(mpx:eGFP) larvae at 48 hpf.