DNA 甲基化微阵列鉴定出患有高胆固醇血症的肥胖患者中受表观遗传调控的脂质相关基因。
DNA methylation microarrays identify epigenetically regulated lipid related genes in obese patients with hypercholesterolemia.
机构信息
Department of Clinical Biochemistry, Jagiellonian University Medical College, Kopernika 15a, 31-501, Kraków, Poland.
Department of Metabolic Diseases, Jagiellonian University Medical College, Kopernika 15a, 31-501, Kraków, Poland.
出版信息
Mol Med. 2020 Oct 7;26(1):93. doi: 10.1186/s10020-020-00220-z.
BACKGROUND
Epigenetics can contribute to lipid disorders in obesity. The DNA methylation pattern can be the cause or consequence of high blood lipids. The aim of the study was to investigate the DNA methylation profile in peripheral leukocytes associated with elevated LDL-cholesterol level in overweight and obese individuals.
METHODS
To identify the differentially methylated genes, genome-wide DNA methylation microarray analysis was performed in leukocytes of obese individuals with high LDL-cholesterol (LDL-CH, ≥ 3.4 mmol/L) versus control obese individuals with LDL-CH, < 3.4 mmol/L. Biochemical tests such as serum glucose, total cholesterol, HDL cholesterol, triglycerides, insulin, leptin, adiponectin, FGF19, FGF21, GIP and total plasma fatty acids content have been determined. Oral glucose and lipid tolerance tests were also performed. Human DNA Methylation Microarray (from Agilent Technologies) containing 27,627 probes for CpG islands was used for screening of DNA methylation status in 10 selected samples. Unpaired t-test and Mann-Whitney U-test were used for biochemical and anthropometric parameters statistics. For microarrays analysis, fold of change was calculated comparing hypercholesterolemic vs control group. The q-value threshold was calculated using moderated Student's t-test followed by Benjamini-Hochberg multiple test correction FDR.
RESULTS
In this preliminary study we identified 190 lipid related CpG loci differentially methylated in hypercholesterolemic versus control individuals. Analysis of DNA methylation profiles revealed several loci engaged in plasma lipoprotein formation and metabolism, cholesterol efflux and reverse transport, triglycerides degradation and fatty acids transport and β-oxidation. Hypermethylation of CpG loci located in promoters of genes regulating cholesterol metabolism: PCSK9, LRP1, ABCG1, ANGPTL4, SREBF1 and NR1H2 in hypercholesterolemic patients has been found. Novel epigenetically regulated CpG sites include ABCG4, ANGPTL4, AP2A2, AP2M1, AP2S1, CLTC, FGF19, FGF1R, HDLBP, LIPA, LMF1, LRP5, LSR, NR1H2 and ZDHHC8 genes.
CONCLUSIONS
Our results indicate that obese individuals with hypercholesterolemia present specific DNA methylation profile in genes related to lipids transport and metabolism. Detailed knowledge of epigenetic regulation of genes, important for lipid disorders in obesity, underlies the possibility to influence target genes by changing diet and lifestyle, as DNA methylation is reversible and depends on environmental factors. These findings give rise for further studies on factors that targets methylation of revealed genes.
背景
表观遗传学可能导致肥胖患者的脂质紊乱。DNA 甲基化模式可能是导致或引起高血脂的原因。本研究的目的是检测与超重和肥胖个体 LDL 胆固醇升高相关的外周血白细胞中 DNA 甲基化的特征。
方法
为了鉴定差异甲基化基因，我们对 LDL 胆固醇（LDL-CH）升高的肥胖个体（LDL-CH≥3.4mmol/L）与 LDL-CH<3.4mmol/L 的对照组肥胖个体的白细胞进行了全基因组 DNA 甲基化微阵列分析。进行了血清葡萄糖、总胆固醇、高密度脂蛋白胆固醇、甘油三酯、胰岛素、瘦素、脂联素、FGF19、FGF21、GIP 和总血浆脂肪酸含量等生化测试。还进行了口服葡萄糖和脂质耐量测试。使用人类 DNA 甲基化微阵列（来自 Agilent Technologies），其中包含用于检测 10 个选定样本中 DNA 甲基化状态的 27627 个 CpG 岛探针。未配对 t 检验和曼-惠特尼 U 检验用于生化和人体测量参数的统计。对于微阵列分析，通过比较高胆固醇血症组与对照组来计算倍数变化。使用经过修饰的学生 t 检验计算 q 值阈值，然后进行 Benjamini-Hochberg 多重检验校正 FDR。
结果
在这项初步研究中，我们在高胆固醇血症患者与对照组个体之间鉴定出 190 个与脂质相关的 CpG 位点发生了差异甲基化。对 DNA 甲基化谱的分析揭示了多个参与血浆脂蛋白形成和代谢、胆固醇外排和反向转运、甘油三酯降解以及脂肪酸转运和β-氧化的基因位点。在高胆固醇血症患者中发现了调节胆固醇代谢的基因 PCSK9、LRP1、ABCG1、ANGPTL4、SREBF1 和 NR1H2 启动子中 CpG 位点的高甲基化。新发现的受表观遗传调控的 CpG 位点包括 ABCG4、ANGPTL4、AP2A2、AP2M1、AP2S1、CLTC、FGF19、FGF1R、HDLBP、LIPA、LMF1、LRP5、LSR、NR1H2 和 ZDHHC8 基因。
结论
我们的研究结果表明，患有高胆固醇血症的肥胖个体存在与脂质转运和代谢相关的特定 DNA 甲基化特征。对肥胖相关脂质紊乱中重要的基因的表观遗传调控的深入了解，为通过改变饮食和生活方式来影响靶基因提供了可能性，因为 DNA 甲基化是可逆的，并且取决于环境因素。这些发现为进一步研究针对所揭示基因的甲基化的因素提供了依据。
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