DNA Methylation Regulates RGS2-induced S100A12 Expression in Airway Epithelial Cells

Abstract

RGS2 is a key modulator of stress in human airway epithelial cells, especially of hyperresponsiveness and mucin hypersecretion, both of which are features of cystic fibrosis (CF). Because its expression can be modulated through the DNA methylation pathway, we hypothesize that RGS2 is downregulated by DNA hypermethylation in CF airway epithelial cells. This downregulation would then lead to an enhanced inflammatory response. We demonstrated RGS2 transcript and protein downregulation in cultured airway epithelial cells from patients with CF and validated our findings in two CF epithelial cell lines. A methylated DNA immunoprecipitation array showed the presence of methylated cytosine on 13 gene promoters in CF. Among these genes, we confirmed that the RGS2 promoter was hypermethylated by using bisulfite conversion coupled with a methylation-specific PCR assay. Finally, we showed that downregulation of RGS2 in non-CF cells increased the expression of S100A12, a proinflammatory marker. These results highlight the importance of epigenetic regulation in gene expression in CF and show that RGS2 might modulate the inflammatory response in CF through DNA methylation control.

Effectiveness of S100 calcium-binding protein A12 combined with modified early warning score in the clinical diagnosis of adult community-acquired pneumonia

“…As a member of the S100 protein family, S100A12 is mainly expressed in peripheral blood cells, and it can distinguish between acute infections and non-infectious diseases. Moreover, it has shown a good diagnostic value in local and systemic infections ( 21 ). Research shows ( 7 , 21 , 22 ) that S100A12 increases in varying degrees in systemic inflammation (e.g., sepsis, septicemia, and septic shock) and local inflammation (e.g., peritonitis, urinary tract infection, pneumonia, and cystic fibrosis with pulmonary infection).…”

“…Moreover, it has shown a good diagnostic value in local and systemic infections ( 21 ). Research shows ( 7 , 21 , 22 ) that S100A12 increases in varying degrees in systemic inflammation (e.g., sepsis, septicemia, and septic shock) and local inflammation (e.g., peritonitis, urinary tract infection, pneumonia, and cystic fibrosis with pulmonary infection). This protein is a new-generation serum marker used to differentiate among acute infectious diseases.…”

RGS2 is an innate immune checkpoint for TLR4 and Gαq-mediated IFNγ generation and lung injury

“…The mechanisms reducing RGS2 and leading to the emergence of IFNγ-linked transcriptome in AM following endotoxemia need to be clarified. A possibility is that epigenetic mechanisms such as DNA methylation are involved in reducing RGS2 synthesis in AM, as in the LPS injury model (Bouvet et al, 2018; Tuggle et al, 2014).…”