Genome-wide DNA methylation analysis reveals loci that distinguish different types of adipose tissue in obese individuals.
Genome-wide DNA methylation analysis reveals loci that distinguish different types of adipose tissue in obese individuals.
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DOI：
10.1186/s13148-017-0344-4
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发表时间：
2017
影响因子：
5.7
通讯作者：
Langston MA
中科院分区：
文献类型：
--
作者：
Macartney-Coxson D;Benton MC;Blick R;Stubbs RS;Hagan RD;Langston MA
表观遗传机制在环境因素和基因组之间提供了一个接口，并且已知在肥胖等复杂疾病中发挥作用。这些机制，包括DNA甲基化，影响发育，分化和细胞身份的建立的调节。在这里，我们采用两种方法来确定两个白色脂肪组织库之间的差异甲基化在肥胖个体之前和之后胃旁路手术和显着的体重减轻。我们使用（a）传统的配对t检验来分析全基因组DNA甲基化数据，以识别显著差异甲基化的基因座（Bonferroni调整的P ≤ 1 × 10−7）和（B）新的组合算法来识别区分组织类型的基因座。在显著体重减轻之前和之后的脂肪组织类型之间，分别观察到3239和7722个CpG位点的显著差异甲基化，包括784和1129个延伸区域。这些延伸的差异甲基化区域（702）中的绝大多数在两个时间点上是一致的，并且富含在转录调节和/或发育中起作用的基因（例如同源框基因）。其他差异甲基化基因座仅在一个时间点观察到，因此可能突出对肥胖症中观察到的脂肪组织功能障碍重要的基因。在DNA甲基化（皮下脂肪vs网膜）的变化与临床性状的变化之间观察到强相关性（r > 0.75，P ≤ 0.001），特别是PITX 2和空腹血糖内的CpG位点以及ISL 2和HDL内的4个CpG位点。单个CpG位点（cg 00838040，ATP 2C 2）产生了强烈的组织分离，在独立的皮下（n = 681）和网膜（n = 33）脂肪样本中得到了验证。这是第一项报告减肥前后皮下腹部和网膜脂肪全基因组DNA甲基化组比较的研究。我们使用的组合方法是鉴定这些组织之间存在强烈差异的甲基化基因座的有力工具。这项研究为未来的研究提供了坚实的基础，重点是脂肪组织的发育及其在肥胖症中的潜在功能障碍，以及DNA甲基化在这些过程中的作用。本文的在线版本（doi：10.1186/s13148-017-0344-4）包含补充材料，可供授权用户使用。
Epigenetic mechanisms provide an interface between environmental factors and the genome and are known to play a role in complex diseases such as obesity. These mechanisms, including DNA methylation, influence the regulation of development, differentiation and the establishment of cellular identity. Here we employ two approaches to identify differential methylation between two white adipose tissue depots in obese individuals before and after gastric bypass and significant weight loss. We analyse genome-wide DNA methylation data using (a) traditional paired t tests to identify significantly differentially methylated loci (Bonferroni-adjusted P ≤ 1 × 10−7) and (b) novel combinatorial algorithms to identify loci that differentiate between tissue types. Significant differential methylation was observed for 3239 and 7722 CpG sites, including 784 and 1129 extended regions, between adipose tissue types before and after significant weight loss, respectively. The vast majority of these extended differentially methylated regions (702) were consistent across both time points and enriched for genes with a role in transcriptional regulation and/or development (e.g. homeobox genes). Other differentially methylated loci were only observed at one time point and thus potentially highlight genes important to adipose tissue dysfunction observed in obesity. Strong correlations (r > 0.75, P ≤ 0.001) were observed between changes in DNA methylation (subcutaneous adipose vs omentum) and changes in clinical trait, in particular for CpG sites within PITX2 and fasting glucose and four CpG sites within ISL2 and HDL. A single CpG site (cg00838040, ATP2C2) gave strong tissue separation, with validation in independent subcutaneous (n = 681) and omental (n = 33) adipose samples. This is the first study to report a genome-wide DNA methylome comparison of subcutaneous abdominal and omental adipose before and after weight loss. The combinatorial approach we utilised is a powerful tool for the identification of methylation loci that strongly differentiate between these tissues. This study provides a solid basis for future research focused on the development of adipose tissue and its potential dysfunction in obesity, as well as the role DNA methylation plays in these processes. The online version of this article (doi:10.1186/s13148-017-0344-4) contains supplementary material, which is available to authorized users.