Transcription Factors in Eosinophil Development and As Therapeutic Targets

Fulkerson, Patricia C.

doi:10.3389/fmed.2017.00115

Cited by 39 publications

(39 citation statements)

References 64 publications

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“…For example, while Meg/E and Bas/Eo progenitors shared accessibility at GATA2 motifs, Bas/Eo commitment was characterized by SPI1 (PU.1) and CEBPA motif activity, while Meg/E commitment was characterized by MYB, GATA1, and KLF1 motif activity, as previously described ( Fig. 3k) 32,33 . Similarly, while neutrophil progenitors shared increased accessibility at SPI1 motifs with Bas/Eo progenitors, neutrophil commitment was accompanied by additional activity of AP-1 and CEBP motifs, and of RARA ( Fig.…”

Section: Regulatory Trajectories Of Immune Lineagessupporting

confidence: 73%

Massively parallel single-cell chromatin landscapes of human immune cell development and intratumoral T cell exhaustion

Satpathy

Granja

Yost

et al. 2019

Preprint

183

284

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Understanding complex tissues requires single-cell deconstruction of gene regulation with precision and scale. Here we present a massively parallel droplet-based platform for mapping transposase-accessible chromatin in tens of thousands of single cells per sample (scATAC-seq). We obtain and analyze chromatin profiles of over 200,000 single cells in two primary human systems. In blood, scATAC-seq allows markerfree identification of cell type-specific cis-and trans-regulatory elements, mapping of disease-associated enhancer activity, and reconstruction of trajectories of differentiation from progenitors to diverse and rare immune cell types. In basal cell carcinoma, scATACseq reveals regulatory landscapes of malignant, stromal, and immune cell types in the tumor microenvironment. Moreover, scATAC-seq of serial tumor biopsies before and after PD-1 blockade allows identification of chromatin regulators and differentiation trajectories of therapy-responsive intratumoral T cell subsets, revealing a shared regulatory program driving CD8 + T cell exhaustion and CD4 + T follicular helper cell development. We anticipate that droplet-based single-cell chromatin accessibility will provide a broadly applicable means of identifying regulatory factors and elements that underlie cell type and function.

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Section: Regulatory Trajectories Of Immune Lineagessupporting

confidence: 73%

Massively parallel single-cell chromatin landscapes of human immune cell development and intratumoral T cell exhaustion

Satpathy

Granja

Yost

et al. 2019

Preprint

183

284

View full text Add to dashboard Cite

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“…43,44 Upon entry into circulation, eosinophils have a short half-life before distribution into diverse tissue sites, including the lung. 43,44 Upon entry into circulation, eosinophils have a short half-life before distribution into diverse tissue sites, including the lung.…”

Section: Discussionmentioning

confidence: 99%

“…Blood eosinophils are derived from an eosinophil lineage-committed progenitor that requires the transcription factor GATA-1. 43,44 Upon entry into circulation, eosinophils have a short half-life before distribution into diverse tissue sites, including the lung. Eosinophil survival transit time in the intravascular space and distribution into tissue sites is modified by numerous factors, 31,43 and the multitude of steps that determine intravascular time make it likely that there would be variability in blood levels in an individual.…”

Section: Discussionmentioning

confidence: 99%

Variability of blood eosinophils in patients in a clinic for severe asthma

Rakowski

Zhao

Liu

et al. 2019

Clin Experimental Allergy

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Background: Blood eosinophils are used to determine eligibility for agents targeting IL-5 in patients with uncontrolled asthma. However, little is known about the variability of blood eosinophil measures in these patients before treatment initiation.Objective: To characterize variability and patterns of variability of blood eosinophil levels in a real-world clinic for severe asthmatics.Methods: Retrospective review of blood eosinophils measured over a 5-year period in patients enrolled in an urban clinic. Repeated measures of blood eosinophil levels in individuals were evaluated, and cluster analysis was performed to characterize patients by eosinophil patterns. Clinical characteristics associated with eosinophil levels and patterns of variability were analysed. Results:Patients treated in the Bellevue Hospital Asthma Clinic within a 3-month period were identified (n = 219). Blood eosinophil measures were obtained over the previous 5 years. Only 6% (n = 13) of patients had levels that were consistently above 300 cells/μL. Nearly 50% (n = 104) had eosinophil levels that traversed the threshold of 300 cells/μL. In contrast, 102 (46%) had levels that never reached the threshold of 300 cells/μL. Cluster analyses revealed three clusters with differing patterns of levels and variability. There was a suggestion of decreased clinical control and increased atopy in the cluster with the greatest variability in blood eosinophil measures. Conclusion:In an urban clinic for patients referred for uncontrolled asthma, blood measures of eosinophils were variable and showed differing patterns of variability.These data reinforce the need to perform repeated eosinophil blood measures for appropriate designation for therapeutic intervention.

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“…48 Eosinophils are specified early in hematopoiesis, 14 and PU.1 is upregulated in eosinophil progenitor cells. 49 PU.1 is also abundant in differentiated peripheral blood eosinophils. 13 In contrast, the transcription factors predicted to bind in the vicinity of exon 1 of the shorter ARHGEF18 isoform (p114) are more widely expressed.…”

Section: Discussionmentioning

confidence: 99%

Expression of novel “LOCGEF” isoforms of ARHGEF18 in eosinophils

Turton

Wilkerson

Hebert

et al. 2018

Journal of Leukocyte Biology

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Genomic, transcriptomic and proteomic databases indicate that the N-terminal 322 residues encoded by the presumptive LOC100996504 gene, which is adjacent to the ARHGEF18 guanine nucleotide exchange factor gene on chromosome 19, constitute the N-terminal portion of a 1361-residue isoform of ARHGEF18, dubbed LOCGEF-X3. LOCGEF-X3 arises from the use of a leukocyte-specific alternative transcriptional start site and splicing that bypasses the initial noncoding exon of the canonical 1015-residue ARHGEF18 isoform, p114. Eosinophil LOCGEF-X3 was amplified and cloned, recombinant LOCGEF-X3 was expressed, and anti-ARHGEF18 antibody was found to recognize a band in immunoblots of eosinophil lysates that co-migrates with recombinant LOCGEF-X3. PCR of eosinophils revealed minor amounts of transcripts for X4 and X5 isoforms of LOCGEF that arise from differential splicing and differ from the X3 isoform at their extreme N-termini. No p114 transcript or protein band was detected in eosinophils. Immunostaining with anti-ARHGEF18 antibody revealed relocalization of LOCGEF and RHOA from the periphery of round unstimulated eosinophils to the 2 poles of eosinophils polarized by treatment with IL5, CCL11, or IL33 in suspension. Canonical p114 ARHGEF18 has been implicated in maintenance of epithelial cell polarity. We suggest that the "LOC" portion of LOCGEF, which is unlike any other protein domain, has unique functions in control of polarity in activated eosinophils and other leukocytes.

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Transcription Factors in Eosinophil Development and As Therapeutic Targets

Cited by 39 publications

References 64 publications

Massively parallel single-cell chromatin landscapes of human immune cell development and intratumoral T cell exhaustion

Massively parallel single-cell chromatin landscapes of human immune cell development and intratumoral T cell exhaustion

Variability of blood eosinophils in patients in a clinic for severe asthma

Expression of novel “LOCGEF” isoforms of ARHGEF18 in eosinophils

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