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Genetic susceptibility to PM2.5 exposure drives transcriptional responses in pediatric asthma: insights from single-cell transcriptomics

ABSTRACT: Background. Exposure to fine particulate matter (PM2.5) increases asthma severity and reduces glucocorticoid responsiveness in children, yet the molecular mechanisms underlying PM2.5 sensitivity remain unclear. We previously identified a PM2.5-sensitive asthma phenotype and developed a PM2.5 sensitivity polygenic risk score (sPRS) correlated with asthma exacerbations and lung function decline. This study expands on these results using genetic mapping and single-cell transcriptomics to elucidate the biological pathways mediating PM2.5 sensitivity and generate hypotheses regarding potential therapeutic targets. Research Question. We aimed to determine whether genetic variants associated with PM2.5 sensitivity converge on specific pathways or transcriptional regulators and assess their role in glucocorticoid responsiveness. Methods. We mapped sPRS variants to genes using regulatory annotation tools and performed pathway enrichment analysis. Single-cell RNA sequencing (scRNA-seq) was conducted on peripheral blood mononuclear cells (PBMCs) from patients stratified by sPRS and matched by PM2.5 exposure to identify transcriptional perturbations in response to PM2.5 exposure. In silico analyses predicted regulatory networks and small molecules that could modulate these pathways. Results. sPRS-associated genes were enriched for SMAD2/3 and MAPK signaling, implicating TGF-β1 as a key mediator of PM2.5 sensitivity. scRNA-seq revealed immune cell-specific transcriptional changes linked to inflammation. Notably, HDM2 inhibition downregulated the PM2.5-sensitive transcriptomic signature, suggesting a role in restoring glucocorticoid responsiveness. Interpretation. Our findings suggest a TGF-β1–HDM2–p53 axis may contribute to PM2.5-induced glucocorticoid resistance and identify HDM2 as a potential therapeutic target for future investigation in PM2.5-sensitive children with asthma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE300837 | GEO | 2026/02/25

REPOSITORIES: GEO

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Project description:Gene expression data of glucocorticoid resistant and sensitive acute lymphoblastic leukemia cell lines for the article: Expression, regulation and function of phosphofructo-kinase/fructose-biphosphatases (PFKFBs) in glucocorticoid-induced apoptosis of acute lymphoblastic leukemia cells Glucocorticoids (GCs) cause apoptosis and cell cycle arrest in lymphoid cells and constitute a central component in the therapy of lymphoid malignancies, most notably childhood acute lymphoblastic leukemia (ALL). PFKFB2 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-2), a kinase controlling glucose metabolism, was identified by us previously as GC response gene in expression profiling analyses performed in children with ALL during initial systemic GC mono-therapy. Since deregulation of glucose metabolism has been implicated in apoptosis induction, this gene and its relatives PFKFB1, 3, and 4 were further analyzed. Expression analyses in additional ALL children, non-leukemic individuals and leukemic cell lines confirmed frequent PFKFB2 induction by GC in most systems sensitive to GC-induced apoptosis, particularly in T-ALL cells. The 3 other family members, in contrast, were not or weakly expressed (PFKFB1 and 4) or not induced by GC (PFKFB3). Conditional PFKFB2 over-expression in the CCRF-CEM T-ALL in vitro model revealed that its 2 splice variants (15A and 15B) did not have any detectable effect on survival or cell cycle progression. Moreover, neither PFKFB2 splice variant significantly affected sensitivity to, or kinetics of, GC-induced apoptosis. Our data suggest that, at least in the model system investigated, PFKFB2 is not an essential upstream regulator of the anti-leukemic effects of GC. Generation of the GC sensitive and resistant clones is described in Parson et al. FASEB J 2005 (Pubmed id 15637111). In brief GC sensitive clones were generated by limiting dilution subcloning from the GC sensitive T-ALL cell line CCRF-CEM-C7H2. To generate GC resistant clones the CCRF-CEM-C7H2 cell line was clutured in the presence of 10E-7 M dexametasone. Gene expression profiles of glucocorticoid (GC) resistant and sensitive T-ALL cells during GC treatment and corresponding control samples (cells treated with carrier control). GC induced regulation of PFKFB2 was determined in the various cell lines based on the expression intensities of the corresponding probe sets in GC treated and control samples.

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Genetic susceptibility to PM2.5 exposure drives transcriptional responses in pediatric asthma: insights from single-cell transcriptomics

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