Variability of genome-wide DNA methylation and mRNA expression profiles in reproductive and endocrine disease related tissues.
Variability of genome-wide DNA methylation and mRNA expression profiles in reproductive and endocrine disease related tissues.
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DOI：
10.1080/15592294.2017.1367475
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Zondervan KT
中科院分区：
文献类型：
--
作者：
Rahmioglu N;Drong AW;Lockstone H;Tapmeier T;Hellner K;Saare M;Laisk-Podar T;Dew C;Tough E;Nicholson G;Peters M;Morris AP;Lindgren CM;Becker CM;Zondervan KT
生殖医学和内分泌学领域的全基因组关联研究正在产生与疾病相关的强大遗传变异。综合基因组学、转录组学和表观基因组学分子谱分析研究是用于了解这些变异体干扰的生物学途径的常用方法。然而，分子分析资源不包括与许多女性生殖特征最相关的组织，子宫内膜，而影响其分子分析结果变异性的参数尚不清楚。我们调查了24名妇女子宫内膜（n = 135）、子宫内膜异位症组织（子宫内膜异位症）和皮下腹部脂肪样本中DNA甲基化和RNA表达谱变异的来源，量化了个体间、组织内（细胞异质性）和技术变异。使用Illumina HumanMethylation 450 BeadChip阵列分析DNA样品（n = 96）;使用H12-表达阵列分析RNA样品（n = 39）。方差分量分析表明，对于前10-50%的可变DNA甲基化/RNA表达位点，个体间变异远远超过组织内变异和技术变异。月经期是子宫内膜甲基化/表达模式的最大变异期（Pm = 7.8 × 10−3，Pe = 8.4 × 10−5），但在脂肪和子宫内膜异位组织中不存在;年龄与子宫内膜DNA甲基化谱显著相关（Pm = 9 × 10−5）和脂肪组织（Pm = 2.4 × 10−5）;吸烟与脂肪组织中的DNA甲基化显著相关（Pm = 1.8 × 10−3）。分层聚类分析显示子宫内膜和子宫内膜异位组织之间的甲基化特征显著不同，富含WNT信号传导、血管生成、钙粘蛋白信号传导和促性腺激素释放激素受体途径。差异DNA甲基化/表达分析表明只能检测到有限数量的具有较大倍数变化（FC > 4）的位点，但考虑不同变异来源的功效计算表明，为了进行稳健的检测，需要>500个组织样本。这些结果使适当的研究设计的大规模表达和甲基化组织相关的许多生殖和内分泌性状的分析。
Genome-wide association studies in the fields of reproductive medicine and endocrinology are yielding robust genetic variants associated with disease. Integrated genomic, transcriptomic, and epigenomic molecular profiling studies are common methodologies used to understand the biologic pathways perturbed by these variants. However, molecular profiling resources do not include the tissue most relevant to many female reproductive traits, the endometrium, while the parameters influencing variability of results from its molecular profiling are unclear. We investigated the sources of DNA methylation and RNA expression profile variability in endometrium (n = 135), endometriotic disease tissue (endometriosis), and subcutaneous abdominal fat samples from 24 women, quantifying between-individual, within-tissue (cellular heterogeneity), and technical variation. DNA samples (n = 96) were analyzed using Illumina HumanMethlylation450 BeadChip arrays; RNA samples (n = 39) were analyzed using H12-expression arrays. Variance-component analyses showed that, for the top 10–50% variable DNA methylation/RNA expression sites, between-individual variation far exceeded within-tissue and technical variation. Menstrual-phase accounted for most variability in methylation/expression patterns in endometrium (Pm = 7.8 × 10−3, Pe = 8.4 × 10−5) but not in fat and endometriotic tissue; age was significantly associated with DNA methylation profile of endometrium (Pm = 9 × 10−5) and endometriotic disease tissue (Pm = 2.4 × 10−5); and smoking was significantly associated with DNA methylation in adipose tissue (Pm = 1.8 × 10−3). Hierarchical cluster analysis showed significantly different methylation signatures between endometrium and endometriotic tissue enriched for WNT signaling, angiogenesis, cadherin signaling, and gonadotropin-releasing-hormone-receptor pathways. Differential DNA methylation/expression analyses suggested detection of a limited number of sites with large fold changes (FC > 4), but power calculations accounting for different sources of variability showed that for robust detection >500 tissue samples are required. These results enable appropriate study design for large-scale expression and methylation tissue-based profiling relevant to many reproductive and endocrine traits.
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通讯作者：
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通讯作者：
Ward K