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High fat diet induces aberrant COX‐2 gene expression through demethylation of a transcriptional enhancer at a 5’ upstream region of the gene (800.7)

Cyclooxygenase‐2 (COX‐2) produces prostaglandins that participate in multiple physiological and pathological processes, including the activation of inflammatory responses. Induction of COX‐2 gene expression has been reported to be correlated with DNA hypomethylation. This study characterized a novel enhancer located at an upstream region on the COX‐2 gene and associated alterations of the DNA methylation patterns by high fat diet. Male Sprague‐Dawley rats received a high fat diet at different life stages, including maternal (HF/C), post‐weaning (C/HF), and lifelong (HF/HF). Liver was collected for analysis at 12 wks of age. Results showed that the high fat diet induced the expression of COX‐2 mRNA in all three high fat groups when compared to the control group (C/C). Genome‐wide methylated DNA immunoprecipitation (MeDIP) showed that DNA hypomethylation occurred at an upstream region of distal promoter of COX‐2 gene in all three high fat groups. Site‐specific hypomethylation of CpG in this region was further analyzed by bisulfite sequencing. Luciferase reporter assay demonstrated an enhancer activity of this particular region. Thus, it is likely that exposure to a high fat diet at various stages of life induces COX‐2 expression through the reduction of DNA methylation at an upstream enhancer region of the gene.