Uncovering the DNA methylation landscape in key regulatory regions within the FADS cluster.
Uncovering the DNA methylation landscape in key regulatory regions within the FADS cluster.
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DOI：
10.1371/journal.pone.0180903
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Chilton FH
中科院分区：
文献类型：
--
作者：
Rahbar E;Ainsworth HC;Howard TD;Hawkins GA;Ruczinski I;Mathias R;Seeds MC;Sergeant S;Hixson JE;Herrington DM;Langefeld CD;Chilton FH
脂肪酸去饱和酶(FADS)簇附近和内部的遗传变异与多不饱和脂肪酸(PUFA)的生物合成、几种疾病生物标志物的水平和人类疾病的风险有关。然而，确定这些基因变异影响多不饱和脂肪酸水平的作用机制仍然是一个挑战。利用Illumina 450K芯片，我们先前报道了人类肝组织中单核苷酸多态rs174537与位于FADS1和FADS2之间假定的增强子区域的CpG位点的−甲基化之间存在强烈的等位基因特异性甲基化(p=2.69×10 DNA29)。然而，这个阵列在这个12kb的区域中只有20个CpG站点。为了更好地了解该区域内的甲基化情况，我们对FADS1和FADS2之间的区域进行了亚硫酸氢盐测序。50名男性受试者(27名欧洲裔美国人，23名非裔美国人)的肝组织来自青年动脉粥样硬化病理生物学决定因素(PDAY)研究，并用于确定rs174537的基因和感兴趣区域的甲基化状态。确定了rs174537基因与136个CpG位点甲基化状态的相关性。年龄调整的线性回归被用来评估ASM与rs174537基因的相关性。大多数CpG位点(136个中的117个，86%)表现出高度的甲基化，在三个关键的调控区-FADS1和FADS2的启动子区域以及两个基因之间的一个假定的增强子区域观察到最大的变异。在假定的增强子区域内的8个CpG位点显示与rs174537有显著的ASM关联(FDR p<；0.05)。这些数据支持这样的概念，即遗传和表观遗传因素都调节多不饱和脂肪酸的生物合成，并提出了一些基本问题，如rs174537等遗传变异如何影响远处调节区的DNA甲基化，最终影响组织合成多不饱和脂肪酸的能力。
Genetic variants near and within the fatty acid desaturase (FADS) cluster are associated with polyunsaturated fatty acid (PUFA) biosynthesis, levels of several disease biomarkers and risk of human disease. However, determining the functional mechanisms by which these genetic variants impact PUFA levels remains a challenge. Utilizing an Illumina 450K array, we previously reported strong allele-specific methylation (ASM) associations (p = 2.69×10−29) between a single nucleotide polymorphism (SNP) rs174537 and DNA methylation of CpG sites located in the putative enhancer region between FADS1 and FADS2, in human liver tissue. However, this array only featured 20 CpG sites within this 12kb region. To better understand the methylation landscape within this region, we conducted bisulfite sequencing of the region between FADS1 and FADS2. Liver tissues from 50 male subjects (27 European Americans, 23 African Americans) were obtained from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study, and used to ascertain the genotype at rs174537 and methylation status across the region of interest. Associations between rs174537 genotype and methylation status of 136 CpG sites were determined. Age-adjusted linear regressions were used to assess ASM associations with rs174537 genotype. The majority of CpG sites (117 out of 136, 86%) exhibited high levels of methylation with the greatest variability observed at three key regulatory regions–the promoter regions for FADS1 and FADS2 and a putative enhancer site between the two genes. Eight CpG sites within the putative enhancer region displayed significant (FDR p <0.05) ASM associations with rs174537. These data support the concept that both genetic and epigenetic factors regulate PUFA biosynthesis, and raise fundamental questions as to how genetic variants such as rs174537 impact DNA methylation in distant regulatory regions, and ultimately the capacity of tissues to synthesize PUFAs.
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