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Dryad

CompareRhythms data in healthy and asthmatic airway epithelial cells

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May 02, 2024 version files 76.49 MB

Abstract

Rationale: Cellular circadian rhythms regulate multiple cellular processes and have been hypothesized to influence epithelial function in asthma. Airway resistance has circadian variability in patients with asthma, profiling of circadian rhythms of gene expression in human airway epithelia has not been performed. Organotypic cultures of primary human airway epithelial cells differentiated at an air-liquid interface recapitulate the major cell types of human airway epithelia to allow for evaluation of gene expression not possible in vivo and demonstrate rhythmicity of core circadian genes after temperature synchronization.

Methods:  Primary human airway epithelial cells from 6 healthy children and 6 children with asthma were differentiated an air-liquid interface and circadian rhythms were synchronized using cycled incubator temperature. RNA was harvested every 4 hours and RNA-sequencing performed to measure transcriptome-wide expression, with differential rhythmicity of genes identified using CompareRhythms.

Results: Core circadian genes ARNTL and NR1D1 demonstrated rhythmicity in both healthy and asthmatic airway epithelial cells with maintained phase relationships. In RNAseq data from healthy and asthmatic airway epithelial cells, 646 (4%) of protein-coding genes were rhythmic, with 110 genes exhibiting differential rhythmicity in asthma. Gene set enrichment analysis using EnrichR revealed that genes in circadian rhythm, nuclear receptor, and cell adhesion pathways were rhythmic. Neutrophil chemotaxis, cytokine mediated signaling, and viral protein interactions with cytokine receptor pathways demonstrated differential (gain, loss, or change) rhythmicity in asthma.

Conclusions: Core circadian rhythm genes maintain rhythmicity in healthy and asthmatic human airway epithelia, and regulate cytokine mediated signaling and neutrophil chemotaxis pathways in asthmatic human airway epithelia.