Cross-species analysis identifies conserved transcriptional mechanisms of neutrophil maturation

Abstract

Neutrophils are evolutionarily conserved innate defense cells implicated in diverse pathological processes. Zebrafish models have contributed substantially to our understanding of neutrophil functions, but similarities to human neutrophil maturation have not been characterized limiting applicability to study human disease. We generated transgenic zebrafish strains to distinguish neutrophil maturation grades in vivo and established a high-resolution transcriptional profile of neutrophil maturation. We linked gene expression at each stage to characteristic transcription factors, including C/ebp{beta}, important for late neutrophil maturation. Cross-species comparison of zebrafish, mouse, and human confirmed high molecular similarity in immature stages and discriminated zebrafish-specific from pan-species gene signatures. Applying pan-species neutrophil maturation signatures in RNA-seq data from neuroblastoma patients revealed an association of metastatic tumor cell infiltration in the bone marrow with an increase in mature neutrophils. Our detailed neutrophil maturation atlas provides a valuable resource for studying neutrophil function at different stages across species in health and disease. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=83 SRC="FIGDIR/small/518146v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@d46deaorg.highwire.dtl.DTLVardef@7c2647org.highwire.dtl.DTLVardef@b535eeorg.highwire.dtl.DTLVardef@e7dc38_HPS_FORMAT_FIGEXP M_FIG C_FIG