Arachidonic and oleic acid exert distinct effects on the 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 (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.

脂肪酸代谢异常与可利用度异常是代谢性疾病的标志性特征，而代谢性疾病本身又与异常的DNA甲基化（DNA methylation）谱式密切相关。为阐明脂肪酸在疾病表观遗传学中的作用，我们旨在探究培养细胞中由花生四烯酸（arachidonic acid, AA）或油酸（oleic acid, OA）特异性诱导的DNA甲基化谱式，并将其与已发表的正常及病变组织的甲基化谱式进行对比。我们采用AA或OA刺激THP-1单核细胞，并通过Infinium HumanMethylation450 BeadChip（Illumina）与Human Exon 1.0 ST阵列（Affymetrix）完成检测分析。该数据集的结果在小鼠胚胎成纤维细胞中得到了验证。我们通过标准生物信息学方法与公开数据集开展对比分析。AA与OA分别诱导出复杂的应答模式：在1~200 μM浓度范围内，AA主要引发全基因组DNA高甲基化，而OA则引发全基因组DNA低甲基化，且二者的差异应答在100 μM浓度下达到峰值。AA与OA的差异应答在靶基因的基因体（gene body）区域尤为显著，且该区域的甲基化变化与基因转录水平呈正相关。AA诱导的DNA甲基化谱式与棕榈酸、动脉粥样硬化、糖尿病、肥胖症及自闭症相关的已报道甲基化谱式较为相似，但与OA诱导的谱式差异显著。此外，AA诱导的甲基化谱式中显著富集了与人类动脉粥样硬化分级相关的DNA甲基化特征。生化实验证据表明，β-氧化（β-oxidation）、过氧化物酶体增殖物激活受体α（PPAR-α）及沉默信息调节因子1（sirtuin 1）是AA诱导DNA甲基化变化的重要调控介质。综上，AA与OA对DNA甲基化组（DNA methylome）的调控作用存在显著差异。研究发现AA可参与塑造重要代谢疾病的表观基因组（epigenome），这一发现支持并拓展了当前基于膳食的疾病治疗与预防策略。