Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
Monash Bioinformatics Platform, Monash University, Clayton VIC, Australia.
PLoS One. 2018 Mar 12;13(3):e0193496. doi: 10.1371/journal.pone.0193496. eCollection 2018.
The Illumina Infinium MethylationEPIC provides an efficient platform for profiling DNA methylation in humans at over 850,000 CpGs. Model organisms such as mice do not currently benefit from an equivalent array. Here we used this array to measure DNA methylation in mice. We defined probes targeting conserved regions and performed differential methylation analysis and compared between the array-based assay and affinity-based DNA sequencing of methyl-CpGs (MBD-seq) and reduced representation bisulfite sequencing. Mouse samples consisted of 11 liver DNA from two strains, C57BL/6J (B6) and DBA/2J (D2), that varied widely in age. Linear regression was applied to detect differential methylation. In total, 13,665 probes (1.6% of total probes) aligned to conserved CpGs. Beta-values (β-value) for these probes showed a distribution similar to that in humans. Overall, there was high concordance in methylation signal between the EPIC array and MBD-seq (Pearson correlation r = 0.70, p-value < 0.0001). However, the EPIC probes had higher quantitative sensitivity at CpGs that are hypo- (β-value < 0.3) or hypermethylated (β-value > 0.7). In terms of differential methylation, no EPIC probe detected a significant difference between age groups at a Benjamini-Hochberg threshold of 10%, and the MBD-seq performed better at detecting age-dependent change in methylation. However, the top most significant probe for age (cg13269407; uncorrected p-value = 1.8 x 10-5) is part of the clock CpGs used to estimate the human epigenetic age. For strain, 219 EPIC probes detected significant differential methylation (FDR cutoff 10%) with ~80% CpGs associated with higher methylation in D2. This higher methylation profile in D2 compared to B6 was also replicated by the MBD-seq data. To summarize, we found only a small subset of EPIC probes that target conserved sites. However, for this small subset the array provides a reliable assay of DNA methylation and can be effectively used to measure differential methylation in mice.
Illumina Infinium MethylationEPIC 为人类超过 85 万个 CpG 提供了高效的 DNA 甲基化分析平台。然而，模型生物如老鼠目前并没有受益于等效的阵列。在这里，我们使用该阵列来测量老鼠的 DNA 甲基化。我们定义了靶向保守区域的探针，并进行了差异甲基化分析，并将基于阵列的检测与基于亲和力的甲基化 CpG（MBD-seq）和简化代表性亚硫酸氢盐测序的 DNA 测序进行了比较。老鼠样本包括来自两个品系，C57BL/6J（B6）和 DBA/2J（D2）的 11 个肝脏 DNA，它们在年龄上差异很大。线性回归用于检测差异甲基化。总共，13665 个探针（总探针的 1.6%）与保守的 CpG 对齐。这些探针的β值（β 值）分布与人类相似。总体而言，EPIC 阵列和 MBD-seq 之间的甲基化信号高度一致（Pearson 相关系数 r = 0.70，p 值 < 0.0001）。然而，在β 值较低（β 值 < 0.3）或较高（β 值 > 0.7）的 CpG 处，EPIC 探针具有更高的定量灵敏度。就差异甲基化而言，在 Benjamini-Hochberg 阈值为 10%的情况下，没有 EPIC 探针检测到年龄组之间的显著差异，而 MBD-seq 在检测甲基化随年龄变化方面表现更好。然而，年龄相关性最高的探针（cg13269407；未校正的 p 值= 1.8 x 10-5）是用于估计人类表观遗传年龄的时钟 CpGs 的一部分。对于品系，219 个 EPIC 探针检测到显著的差异甲基化（FDR 截止值为 10%），约 80%的 CpG 与 D2 中更高的甲基化相关。与 B6 相比，D2 中的这种更高的甲基化模式也被 MBD-seq 数据复制。总之，我们只发现了一小部分靶向保守位点的 EPIC 探针。然而，对于这个小部分，阵列提供了一种可靠的 DNA 甲基化分析方法，可以有效地用于测量老鼠的差异甲基化。
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