Transcription Factor Repertoire of Homeostatic Eosinophilopoiesis.
The production of mature eosinophils (Eos) is a tightly orchestrated process with the aim to sustain normal Eos levels in tissues while also maintaining low numbers of these complex and sensitive cells in the blood. To identify regulators of homeostatic eosinophilopoiesis in mice, we took a global approach to identify genome-wide transcriptome and epigenome changes that occur during homeostasis at critical developmental stages, including Eos-lineage commitment and lineage maturation. Our analyses revealed a markedly greater number of transcriptome alterations associated with Eos maturation (1199 genes) than with Eos-lineage commitment (490 genes), highlighting the greater transcriptional investment necessary for differentiation. Eos-lineage-committed progenitors (EoPs) were noted to express high levels of granule proteins and contain granules with an ultrastructure distinct from that of mature resting Eos. Our analyses also delineated a 976-gene Eos-lineage transcriptome that included a repertoire of 56 transcription factors, many of which have never previously been associated with Eos. EoPs and Eos, but not granulocyte-monocyte progenitors or neutrophils, expressed Helios and Aiolos, members of the Ikaros family of transcription factors, which regulate gene expression via modulation of chromatin structure and DNA accessibility. Epigenetic studies revealed a distinct distribution of active chromatin marks between genes induced with lineage commitment and genes induced with cell maturation during Eos development. In addition, Aiolos and Helios binding sites were significantly enriched in genes expressed by EoPs and Eos with active chromatin, highlighting a potential novel role for Helios and Aiolos in regulating gene expression during Eos development.
Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229;
Carine
C
Bouffi
Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229;
Andrey V
AV
Kartashov
Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229;
Kaila L
KL
Schollaert
School of Electronic and Computing Systems, University of Cincinnati, Cincinnati, OH 45221;
Xiaoting
X
Chen
Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229;
W Clark
WC
Bacon
Center for Autoimmune Genomics and Etiology, Division of Biomedical Informatics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229; Division of Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229; and.
Matthew T
MT
Weirauch
Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229; Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229.
Artem
http://orcid.org/0000-0002-1861-5316
A
Barski
Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229; patricia.fulkerson@cchmc.org.
Patricia C
PC
Fulkerson
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics; D003594:Cytoplasmic Granules / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D004804:Eosinophils / Q000166:cytology* / Q000276:immunology; D005786:Gene Expression Regulation / Q000235:genetics; D042381:Granulocyte Precursor Cells; D006410:Hematopoiesis / Q000235:genetics* / Q000276:immunology; D051740:Ikaros Transcription Factor; D051379:Mice; D008807:Mice, Inbred BALB C; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics*
D002843:Chromatin; D004268:DNA-Binding Proteins; C491396:Ikzf3 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C491746:Zfpn1a2 protein, mouse; D051740:Ikaros Transcription Factor