호산구 분화 말기-특이 유전자 Olig2 및 P2Y10의 동정과 특성 규명

Abstract

Eosinophils arise from CD34+ hematopoietic stem cells through commitment, proliferation, differentiation, and functional maturation. A transcriptional network involving GATA1, GATA2, C/EBPs, and PU.1 governs fate decision and subsequent differentiation and maturation of eosinophils. No transcription factor, to date, has been identified that is uniquely expressed in eosinophils. Our previous study has previously identified Olig2 as a transcription factor that is selectively expressed at late stage of eosinophil differentiation, but its transcriptional targets in eosinophils remained unknown.

Eosinophils are highly specialized granulocytes found in blood and also occur in various tissues such as small intestine, uterus, mammary gland, and thymus. They are widely accepted as key effector cells of allergic diseases and more recently emerge to regulate immune and metabolic homeostasis. Eosinophil functions are attributed largely to a wide variety of preformed and de novo inflammatory mediators. In addition, eosinohils express diverse classes of activation receptors to sense external and internal cues for adequate functions. Recent whole genome-wide analyses from our laboratory and others reveal that eosinophils selectively express a multitude of novel genes. However, their functions remained extensively to be characterized.

In the first series of experiments, We discover the gene SIGLEC-8 as a transcriptional target of Olig2 using RNA-seq analysis followed by extensive biochemical and molecular analyses. We find that Olig2 activates SIGLEC-8 transcription by binding to the E-box in the first intron of the gene.

In the second series of experiments, We identify P2Y10 as one of genes that is highly upregulated at late stage of eosinophil differentiation. P2Y10 is a G protein-coupled receptor that is recently deorphanized as a receptor for lysophosphatidylserine (LysoPS) along with other two receptors GPR34 and GPR174. We find that eosinophils express only P2Y10 among the three receptors and that LysoPS triggers eosinophil degranulation, one of the most crucial eosinophil-specific functions.

Identification and functional characterization of these two eosinophil-specific genes extend our understanding of eosinophils, thereby contributing to eosinophil biology.