The Znf711-Phf8 complex functions as a transcriptional rheostat essential for neutrophil development

Neutrophil differentiation is governed by a precise transcriptional and epigenetic program. Here, we identify the zinc finger protein 711 (Znf711) and its partner, the histone demethylase PHD finger protein 8 (Phf8), as essential regulators of terminal granulopoiesis. Contrary to their established role as a transcriptional activatorcoactivator pair, we found that the Znf711-Phf8 complex operates through a repressive mechanism. Znf711 promotes neutrophil maturation in a DNA-binding-independent manner by sequestering Phf8. Upon loss of Znf711, Phf8 is recruited by the growth factor independent 1 transcription repressor (Gfi1aa) to the promoter of the master regulator c/ebpα, where SUMOylated Phf8 acts as a corepressor to inhibit its transcription. Furthermore, we delineate a positive feedback loop wherein C/ebpα directly activates znf711 expression, ensuring a high level of c/ebpα at the onset of differentiation. Our findings define the Znf711-Phf8 complex as a critical transcriptional rheostat in neutrophil development.