Arachidonic and Oleic Acid Exerts Distinct Effects on DNA Methylome

Abnormal fatty acid metabolism and availability are landmarks of metabolic diseases, which in turn are associated with aberrant DNA methylation profiles. To understand the role of fatty acids in disease epigenetics, we sought DNA methylation profiles specifically induced by arachidonic or oleic acid (AA and OA) in cultured cells and compared those with published profiles of normal and diseased tissues. THP‐1 monocytes were stimulated with AA or OA and analyzed using Infinium HumanMethylation450 BeadChip (Illumina) and Human Exon 1.0 ST array (Affymetrix). Data were corroborated in mouse embryonic fibroblasts. Comparisons with publicly available data were conducted by standard bioinformatics. AA and OA elicited a complex response marked by a general DNA hyper‐ and hypomethylation in the 1–200 μM range, respectively, with a maximal differential response at the 100 μM dose. The divergent response to AA and OA was prominent within the gene body of target genes, where it correlated positively with transcription. AA‐induced DNA methylation profiles were similar to the corresponding profiles described for palmitic acid, atherosclerosis, diabetes, obesity and autism, but relatively dissimilar from OA‐induced profiles. A set of genes was identified, that display gene body hypermethylation in response to AA and in human atherosclerosis. Biochemical evidence pointed to beta‐oxidation, PPAR‐alpha and sirtuin 1 as important mediators of AA‐induced DNA methylation changes. In conclusion, AA and OA exert distinct effects on the DNA methylome. The observation that AA may contribute to shape the epigenome of important metabolic diseases supports and expands current diet‐based therapeutic and preventive efforts. Support or Funding Information CONCyTEG grant no. 08‐03‐K662‐020‐A01, Mexican Council for Science and Technology (CONACyT) Basic Science (Ciencia Básica) grant no. 83401 to GL; CONACyT Sabbatical Fellowships no. 166209 to G.L. and no. 166058 to S.Z.; CONACyT Ph.D. Fellowship no. 334370 to G.A.S.‐M.; the Spanish Ministry of Ministry of Economy and Competitiveness (MINECO) grant SAF2011‐25619 to A.V.