Abstract
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.
Highlights
There has been a surge in large-scale epigenetic studies in recent years
A remarkable biological insight that has emerged from these array-based studies is the definition of the methylation-based “epigenetic clock,” a biomarker of human age and aging that is defined using specific probes represented on these arrays [8]
CpG island annotations [19] for the respective genome were downloaded from UCSC Genome Browser and distribution of conserved probes and positions of CpG islands (CGIs) were plotted to the human (GRCh37) and mouse genomes using CIRCOS [20]
Summary
Epigenome-wide association studies (EWAS) of DNA methylation have shown associations with physiological traits [1, 2], diseases [3,4,5], environmental exposures [6, 7], aging [8], and even socioeconomic [9] and emotional experiences [10]. The Illumina Human Methylation BeadChips have made it both convenient and cost-effective to incorporate an epigenetic arm to large epidemiological studies [11, 12]. The latest version, the Illumina Infinium MethylationEPIC BeadChip (EPIC), provides an efficient high throughput platform to quantify methylation at 866,836 CpG sites on the human genome [13, 14]. A remarkable biological insight that has emerged from these array-based studies is the definition of the methylation-based “epigenetic clock,” a biomarker of human age and aging (i.e., the epigenetic clock) that is defined using specific probes represented on these arrays [8]
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