ThPOK is a critical multifaceted regulator of myeloid lineage development

Basu et al. find that the transcription factor ThPOK is not restricted to T cells, as it also is expressed in myeloid cell progenitors and contributes to the lineage choice of monocyte-dendritic cells as opposed to neutrophils. The transcription factor ThPOK (encoded by Zbtb7b) is well known for its role as a master regulator of CD4 lineage commitment in the thymus. Here, we report an unexpected and critical role of ThPOK as a multifaceted regulator of myeloid lineage commitment, differentiation and maturation. Using reporter and knockout mouse models combined with single-cell RNA-sequencing, progenitor transfer and colony assays, we show that ThPOK controls monocyte-dendritic cell versus granulocyte lineage production during homeostatic differentiation, and serves as a brake for neutrophil maturation in granulocyte lineage-specified cells through transcriptional regulation of lineage-specific transcription factors and RNA via altered messenger RNA splicing to reprogram intron retention.

Automated summary

Basu et al. discovered that the transcription factor ThPOK plays a crucial role in myeloid lineage commitment, differentiation, and maturation. It is not only expressed in T cells but also in myeloid cell progenitors, and influences the choice between monocyte-dendritic cells and neutrophils. ThPOK controls granulocyte lineage production, acts as a brake for neutrophil maturation, and regulates lineage-specific transcription factors and RNA through altered messenger RNA splicing.