Abstract 4222: Omega-3 fatty acids produce DNA methylation changes in inflammation-related genes and pathways with implication of toll-like receptor signaling

Abstract

Abstract Introduction Omega-3 polyunsaturated fatty acids (n-3 PUFA) have been studied for potential health benefits in many diseases including breast cancer. The preventive effects of n-3 PUFAs may relate in part to inhibition of chronic, low-grade inflammation. Of interest is the role of n-3 PUFAs in modulating pro-inflammatory gene expression via epigenetic factors such as DNA methylation (DNAm). Methods DNA methylation of PBMCs obtained at 0 and 6 months of n-3 PUFA supplementation was assessed via reduced representation bisulfite sequencing (RRBS). PBMC samples were obtained from women at high risk for breast cancer during a randomized clinical trial investigating the effects of different n-3 PUFA doses. The dosing arm selected for this study was 5 g of EPA+DHA/day, with baseline and 6 month samples (n=10). DNAm was quantified using Bismark from trimmed, pass filter reads and analyzed with MethylKit to determine n-3 PUFA treatment specific DNAm changes. Results Global DNAm showed no change after 6 months of n-3 PUFA treatment; however, we detected 30,974 differentially methylated CpGs (DMCs) across the genome. DMCs, both genome-wide and in gene promoters, where DNAm can regulate gene expression, were significantly enriched for hypermethylation events after treatment. Focusing the analysis on pro-inflammatory signaling mediators led to identification of candidate gene promoter DMCs involved in several inflammation-related pathways. Four pathways were significantly enriched for both DMCs and DMC hypermethylation events even when accounting for the genome-wide trend toward hypermethylated DMCs (hypergeometric test p-value < 0.001). The Toll-Like Receptor Pathway (TLR) genes harbored the most DNAm changes post n-3 PUFA treatment. Conclusion Our findings demonstrate that n-3 PUFA supplementation can result in inflammation-related changes stemming from PBMC methylome perturbation. The results suggest the TLR pathway as a potential mechanism for the anti-inflammatory effects of EPA and DHA. Functional studies are needed to confirm our current observation. Citation Format: David E. Frankhouser, Sarah Woelke, Michael Sovic, Ralf Bundschuh, Pearlly Yan, Lisa D. Yee. Omega-3 fatty acids produce DNA methylation changes in inflammation-related genes and pathways with implication of toll-like receptor signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4222.