Authors:

Rebecca J. Sias

Date Created:

Not specified

Course Title:

Professor:

Not specified

About Paper:

Asthma is a chronic inflammatory disease driven by complex gene-environment interactions that differ by relevant airway cell types. Airway smooth muscle cells (ASMCs) are a key cell type in asthma that is responsible for airway hyperresponsiveness (AHR), the increased contractility in response to inhaled irritants that causes wheezing and shortness of breath. To investigate how inflammatory cytokines regulate ASMC function, we cultured and exposed primary ASMCs from 69 lung donors to interleukins 13 and 17 (IL-13 and IL-17) and vehicle, and quantitatively investigated their effects on gene expression and methylation in a subset of 26,659 likely functional CpGs from the EPIC array. Using matrixeQTL, we identified statistically significant associations between gene expression and methylation levels at nearby CpGs (+125Kb), also known as eQTMs. Pathway analysis of significant CoGs and genes corresponding to each treatment showed enrichment in biological processes and traits relevant to airway inflammation and remodeling (such as fractional exhaled nitric oxide and atopy). We also found that when donor sex and asthma status were incorporated as interaction terms in the eQTM model, these terms modulated the association strength and direction of significant CpG-gene pairs (n=1,374 unique pairs for sex and 1,665 for asthma across conditions; fdr < 0.05). These results lead us to believe that cytokine treatment effects in ASMCs are mediated by more complex mechanisms than a causal methylation-expression relationship. In conclusion, these studies address a significant gap in genomic studies in asthma by exploring epigenetic regulation in a critical but understudied cell type. Our findings will enhance understanding of potential molecular mechanisms linking environmental exposures (such as asthma-inducing cytokines) to disease, and add to the arsenal of approaches used to analyze genomics data in complex disease research.

Source:

University of Chicago

Topics:

No topics listed

Co-authors:

Rebecca J. Sias