Biology subjects

Adcock, I.

Publications and source records attributed to Adcock, I..

2 recordsLinked to original sources

bioRxiv2026

Lung function candidate genes in Drosophila melanogaster

RationaleChronic obstructive pulmonary disease (COPD) represents a leading cause of global morbidity and mortality. Genome-wide association studies (GWAS) have implicated numerous genetic variants in lung function impairment, yet confidently identifying the underlying genes and pathways, and translating these findings into mechanistic insight, remains a significant challenge. ObjectivesTo leverage the genetic amenability and high-throughput screening capability of Drosophila melanogaster to determine the role of candidate causal genes in epithelial cell homeostasis. MethodsWe performed a loss-of-function analysis of 60 prioritised lung function candidate causal genes implicated from GWAS in two distinct epithelia: the dorsal thorax and trachea. ResultsWe identified 57/60 tested candidate genes that alter at least one aspect of epithelial morphology and behaviour upon knockdown. With a focus on junctional integrity, cell delamination and tissue growth, we identified 11 genes for further study: Sec6, RpS26, pAbp, Arf102f, Riok1, Sra-1, Inpp5e, CG31759, ssh, eIF6 and Rtf1. Further characterisation found a significant reduction in junctional E-Cadherin levels following Arf102F, Rtf1, RioK1 and Sra-1 knockdown. Following a secondary screen in the Drosophila tracheal system for priority candidates, Sec6 and RpS26 were associated with significant airway defects and a reduction in larval body size. 8/11 priority genes exhibited differential lung gene expression between controls and patients with COPD. ConclusionsThese data demonstrate the amenability of Drosophila melanogaster to perform in vivo functional analyses of candidate causal genes at scale. Initial findings implicate several genes in epithelial homeostasis and integrity, providing new mechanistic understanding and potential therapeutic targets for COPD. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=164 SRC="FIGDIR/small/731340v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@dbff6dorg.highwire.dtl.DTLVardef@15e84f0org.highwire.dtl.DTLVardef@69d97aorg.highwire.dtl.DTLVardef@144f47e_HPS_FORMAT_FIGEXP M_FIG C_FIG

Cell Biology↗

bioRxiv2022

IL-33 induced gene expression in activated Th2 effector cells is dependent on IL-1RL1 haplotype and disease status

BackgroundIL-33 can activate Th2 cells after binding to the IL-1RL1/IL-1RAcP receptor. However, it is unknown whether disease or genetic make-up regulate IL33 responsiveness of Th2 cells. ObjectiveWe investigated whether IL-1RL1 asthma risk haplotypes or asthma status influence IL-33-induced Th2 transcriptomic responses in vitro. MethodsCD4+ T cells from 16 asthma patients and matched controls, stratified for IL-1RL1 haplotype, were differentiated into Th2 effector cells, and re-stimulated in the presence or absence of IL-33, followed by RNA-sequencing and differential gene expression analysis. Association of IL-33-induced gene signatures with clinical parameters was tested in U-BIOPRED sputum transcriptomic data. ResultsPresence of IL-33 during Th2 cell re-stimulation results in extensive changes in gene expression, affecting a large proportion of the activated Th2 cell transcriptome. IL-33 induced more genes in Th2 cells from donors with asthma than in controls. However, the IL-33 effects were strongest in Th2 cells carrying the IL-1RL1 risk haplotype, as evidenced by a significantly increased effect size compared to controls. A gene signature of IL-33 induced genes in Th2 cells showed a strong positive correlation with macrophage counts and pauci-granulocytic asthma in sputum transcriptomic data from the U-BIOPRED study. ConclusionThe risk IL-1RL1 haplotype strongly increases the sensitivity of Th2 effector cell for IL-33-mediated regulation of gene expression, while asthma status has an independent effect. The IL-33 gene signature was not associated with type-2 high or eosinophilic asthma in sputum transcriptomic data from U-BIOPRED. Clinical OutcomeCellular sensitivity to IL-33 depends on genetic makeup and asthma disease status. Capsule summaryIL-33 strongly alters gene expression of activated Th2 cells, dependent on asthma disease status and IL-1RL1 risk haplotype. IL-33 driven gene signature in sputum transcriptomic data identifies pauci-granulocytic asthma.

molecular biology↗