Hematopoietic Overexpression of FOG1 Does Not Affect B-Cells but Reduces the Number of Circulating Eosinophils

Roure, Camille Du; Versavel, Aude; Doll, Thierry; Cao, Chun; Pillonel, Vincent; Matthias, Gabriele; Kaller, Markus; Spetz, Jean-François; Kopp, Patrick; Kohler, Hubertus; Müller, Matthias; Matthias, Patrick

doi:10.1371/journal.pone.0092836

Cited by 7 publications

(6 citation statements)

References 51 publications

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“…FOG-1 is a transcriptional cofactor that facilitates binding of GATA factors to DNA and recruits chromatin remodeling complexes ( 12 – 14 ). FOG-1 is highly expressed by multipotent progenitors, antagonizes GATA-1 transcriptional activity, and must be downregulated to allow for eosinophil lineage commitment ( 15 , 16 ). Loss of FOG-1 expression in mice is early embryonic lethal from severe anemia due to the requirement for FOG-1 for the formation of erythroid-lineage progenitors ( 17 ).…”

Section: Eosinophil Lineage Commitmentmentioning

confidence: 99%

Transcription Factors in Eosinophil Development and As Therapeutic Targets

Fulkerson

2017

Front. Med.

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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.

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Section: Eosinophil Lineage Commitmentmentioning

confidence: 99%

Transcription Factors in Eosinophil Development and As Therapeutic Targets

Fulkerson

2017

Front. Med.

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“…Prior to circulation and recruitment to the tissue, eosinophilopoiesis originates from a granulocytes/macrophage progenitor (GMP) precursor, followed by maturation of eosinophil lineage–committed progenitor cells (EoPs). Eosinophil development occurs in the bone marrow via decisive steps in cell fate driven by the action of primary lineage-determining transcription factors (TFs), including GATA-1, GATA-2, PU.1, CEBPα, FOG1 and IRF8 4 – 8 . Subsequently, the EoP lineage commitment is reinforced, either in the bone marrow or tissue, by secondary TFs that orchestrate gene expression, differentiation and maturation into eosinophils, including the TFs CEBPε and XBP1 9 – 11 .…”

Section: Introductionmentioning

confidence: 99%

Aiolos regulates eosinophil migration into tissues

et al. 2021

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Expression of Ikaros family transcription factor IKZF3 (Aiolos) increases during murine eosinophil lineage commitment and maturation. Herein, we investigated Aiolos expression and function in mature human and murine eosinophils. Murine eosinophils deficient in Aiolos demonstrated gene expression changes in pathways associated with granulocyte-mediated immunity, chemotaxis, degranulation, ERK/MAPK signaling and extracellular matrix organization; these genes had ATAC peaks within 1 kB of the TSS that were enriched for Aiolos binding motifs. Global Aiolos deficiency reduced eosinophil frequency within peripheral tissues during homeostasis; a chimeric mouse model demonstrated dependence on intrinsic Aiolos expression by eosinophils. Aiolos deficiency reduced eosinophil CCR3 surface expression, intracellular ERK1/2 signaling and CCL11-induced actin polymerization, emphasizing an impaired functional response. Aiolos-deficient eosinophils had reduced tissue accumulation in chemokine-, antigen-, and IL-13–driven inflammatory experimental models, all of which at least partially depend on CCR3 signaling. Human Aiolos expression was associated with active chromatin marks enriched for IKZF3, PU.1 and GATA-1 binding motifs within eosinophil-specific histone ChIP-seq peaks. Furthermore, treating the EOL-1 human eosinophilic cell line with lenalidomide yielded a dose-dependent decrease in Aiolos. These collective data indicate that eosinophil homing during homeostatic and inflammatory allergic states is Aiolos dependent, identifying Aiolos as a potential therapeutic target for eosinophilic disease.

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“…Other TFs, including friend of GATA-1 (FOG-1) and interferon regulatory factor 8 (IRF8), regulate Gata1 expression. FOG-1 is highly expressed by HPCs, acts to antagonize GATA-1, and must be down-regulated for eosinophil differentiation to proceed [ 15 , 16 , 17 ]. In contrast, loss of IRF8 expression attenuates EoP frequency and Gata1 expression [ 18 ].…”

Section: Regulation Of Eosinophilopoiesismentioning

confidence: 99%

Eosinophil Lineage-Committed Progenitors as a Therapeutic Target for Asthma

Salter

Sehmi

2021

Cells

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Eosinophilic asthma is the most prevalent phenotype of asthma. Although most asthmatics are adequately controlled by corticosteroid therapy, a subset (5–10%) remain uncontrolled with significant therapy-related side effects. This indicates the need for a consideration of alternative treatment strategies that target airway eosinophilia with corticosteroid-sparing benefits. A growing body of evidence shows that a balance between systemic differentiation and local tissue eosinophilopoietic processes driven by traffic and lung homing of bone marrow-derived hemopoietic progenitor cells (HPCs) are important components for the development of airway eosinophilia in asthma. Interleukin (IL)-5 is considered a critical and selective driver of terminal differentiation of eosinophils. Studies targeting IL-5 or IL-5R show that although mature and immature eosinophils are decreased within the airways, there is incomplete ablation, particularly within the bronchial tissue. Eotaxin is a chemoattractant for mature eosinophils and eosinophil-lineage committed progenitor cells (EoP), yet anti-CCR3 studies did not yield meaningful clinical outcomes. Recent studies highlight the role of epithelial cell-derived alarmin cytokines, IL-33 and TSLP, (Thymic stromal lymphopoietin) in progenitor cell traffic and local differentiative processes. This review provides an overview of the role of EoP in asthma and discusses findings from clinical trials with various therapeutic targets. We will show that targeting single mediators downstream of the inflammatory cascade may not fully attenuate tissue eosinophilia due to the multiplicity of factors that can promote tissue eosinophilia. Blocking lung homing and local eosinophilopoiesis through mediators upstream of this cascade may yield greater improvement in clinical outcomes.

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Hematopoietic Overexpression of FOG1 Does Not Affect B-Cells but Reduces the Number of Circulating Eosinophils

Cited by 7 publications

References 51 publications

Transcription Factors in Eosinophil Development and As Therapeutic Targets

Transcription Factors in Eosinophil Development and As Therapeutic Targets

Aiolos regulates eosinophil migration into tissues

Eosinophil Lineage-Committed Progenitors as a Therapeutic Target for Asthma

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