title: Arachidonic and oleic acid exert distinct effects on the DNA methylome.
abstract: 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 (AA) or oleic acid (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 hypermethylation 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. Furthermore, human atherosclerosis grade-associated DNA methylation profiles were significantly enriched in AA-induced profiles. Biochemical evidence pointed to β-oxidation, PPAR-α, 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.
authors.affiliation: a Department of Genetic Engineering , CINVESTAV Irapuato Unit , Irapuato , Mexico.
authors.forename: Guillermo A
authors.initials: GA
authors.lastname: Silva-Martínez
authors.affiliation: a Department of Genetic Engineering , CINVESTAV Irapuato Unit , Irapuato , Mexico.
authors.forename: Dalia
authors.initials: D
authors.lastname: Rodríguez-Ríos
authors.affiliation: b Department of Medical Sciences , Division of Health Sciences, León Campus, University of Guanajuato , Mexico.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Alvarado-Caudillo
authors.affiliation: c Laboratory of Chromatin Biology, Cancer Epigenetics and Biology Program (PEBC) , IDIBELL, L'Hospitalet de Llobregat , Barcelona , Catalonia , Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Vaquero
authors.affiliation: d Laboratory of Cancer Epigenetics, Cancer Epigenetics and Biology Program (PEBC) , IDIBELL, L'Hospitalet de Llobregat , Barcelona , Catalonia , Spain.
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.affiliation: d Laboratory of Cancer Epigenetics, Cancer Epigenetics and Biology Program (PEBC) , IDIBELL, L'Hospitalet de Llobregat , Barcelona , Catalonia , Spain.
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Carmona
authors.affiliation: d Laboratory of Cancer Epigenetics, Cancer Epigenetics and Biology Program (PEBC) , IDIBELL, L'Hospitalet de Llobregat , Barcelona , Catalonia , Spain.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Moran
authors.affiliation: e Center for Genomic Medicine, Rigshospitalet , University of Copenhagen , Copenhagen , Denmark.
authors.forename: Finn C
authors.initials: FC
authors.lastname: Nielsen
authors.affiliation: f Experimental Cardiovascular Research , Malmö University Hospital, Lund University , Malmö , Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Wickström-Lindholm
authors.affiliation: g Department of Chemistry, Division of Natural and Exact Sciences, Guanajuato Campus , University of Guanajuato , Mexico.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Wrobel
authors.affiliation: g Department of Chemistry, Division of Natural and Exact Sciences, Guanajuato Campus , University of Guanajuato , Mexico.
authors.forename: Kazimierz
authors.initials: K
authors.lastname: Wrobel
authors.affiliation: b Department of Medical Sciences , Division of Health Sciences, León Campus, University of Guanajuato , Mexico.
authors.forename: Gloria
authors.initials: G
authors.lastname: Barbosa-Sabanero
authors.affiliation: b Department of Medical Sciences , Division of Health Sciences, León Campus, University of Guanajuato , Mexico.
authors.forename: Silvio
authors.initials: S
authors.lastname: Zaina
authors.affiliation: a Department of Genetic Engineering , CINVESTAV Irapuato Unit , Irapuato , Mexico.
authors.forename: Gertrud
authors.initials: G
authors.lastname: Lund
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000008:administration & dosage / Q000378:metabolism*; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019175:DNA Methylation / Q000187:drug effects*; D044127:Epigenesis, Genetic / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015894:Genome, Human; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D019301:Oleic Acid / Q000008:administration & dosage / Q000378:metabolism*; D047493:PPAR alpha / Q000235:genetics
chemical_list: D047493:PPAR alpha; D016718:Arachidonic Acid; D019301:Oleic Acid
keywords: DNA methylation; PPAR; epigenomics; fatty acid; sirtuin; β-oxidation