Abstract

Dynamic gene expression is a major regulatory mechanism that directs hematopoietic cell fate and differentiation, including eosinophil lineage commitment and eosinophil differentiation. Though GATA-1 is well established as a critical transcription factor (TF) for eosinophil development, delineating the transcriptional networks that regulate eosinophil development at homeostasis and in inflammatory states is not complete. Yet, recent advances in molecular experimental tools using purified eosinophil developmental stages have led to identifying new regulators of gene expression during eosinophil development. Herein, recent studies that have provided new insight into the mechanisms of gene regulation during eosinophil lineage commitment and eosinophil differentiation are reviewed. A model is described wherein distinct classes of TFs work together via collaborative and hierarchical interactions to direct eosinophil development. In addition, the therapeutic potential for targeting TFs to regulate eosinophil production is discussed. Understanding how specific signals direct distinct patterns of gene expression required for the specialized functions of eosinophils will likely lead to new targets for therapeutic intervention.

Highlights

  • Eosinophils differentiate in the bone marrow from an eosinophil lineage-committed progenitor (EoP) that is derived from the granulocyte/macrophage progenitor (GMP) in mice and the common myeloid progenitor or an upstream multipotent progenitor in humans [1, 2]

  • A wealth of evidence support a critical role for the cytokine IL-5 in mediating disease-associated eosinophilia, and neutralizing IL-5 indirectly suppresses eosinophil maturation [54]

  • IL-5 is produced by type 2 helper T (Th2) cells and the transcription factors (TFs) GATA-3 has been shown to control expression of IL-5 in Th2 cells [55]

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Summary

INTRODUCTION

Eosinophils differentiate in the bone marrow from an eosinophil lineage-committed progenitor (EoP) that is derived from the granulocyte/macrophage progenitor (GMP) in mice and the common myeloid progenitor or an upstream multipotent progenitor in humans [1, 2]. It is well established that myeloid progenitor expression of the TF GATA-1 is essential for eosinophil lineage commitment [6,7,8,9] Though the PU. expression level in myeloid progenitors has been shown to be important in regulating macrophage and neutrophil cell fates [3, 31], a definitive early role for PU. in eosinophil lineage commitment has not been defined. Gene expression analysis of PU.1-deficient fetal liver cells revealed expression of eosinophil peroxidase and major basic protein (Prg2), but little to no Il5ra [32], suggesting that PU. is not essential for eosinophil lineage commitment, but studies with a specific focus on the eosinophil lineage potential of hematopoietic cells deficient in PU. are needed

Summary of Eosinophil Lineage Commitment
CONCLUSION AND FUTURE DIRECTIONS
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