Although alterations in DNA methylation patterns have been associated with specific diseases and environmental exposures, the mediators and signaling pathways that direct these changes remain understudied. The bioactive lipid mediator prostaglandin E 2 (PGE 2) has been shown to exert a myriad of effects on cell survival, proliferation, and differentiation. Here, we report that PGE 2 also signals to increase global DNA methylation and DNA methylation machinery in fibroblasts. HumanMethylation27 BeadChip array analysis of primary fetal (IMR-90) and adult lung fibroblasts identified multiple genes that were hypermethylated in response to PGE 2.
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PGE 2, compared with nontreated controls, increased expression and activity (EC 50∼10 7 M) of one specific isoform of DNA methyltransferase, DNMT3a. Silencing of DNMT3a negated the ability of PGE 2 to increase DNMT activity. The increase in DNMT3a expression was mediated by PGE 2 signaling via its E prostanoid 2 receptor and the second messenger cAMP.