Abstract
To study the impact of aging on DNA methylation and mRNA expression in human liver. We analysed genome-wide DNA methylation and gene expression in human liver samples using Illumina 450K and HumanHT12 expression BeadChip arrays. DNA methylation analysis of ∼455,000 CpG sites in human liver revealed that age was significantly associated with altered DNA methylation of 20,396 CpG sites. Comparison of liver methylation data with published methylation data in other tissues showed that vast majority of the age-associated significant CpG sites overlapped between liver and blood, whereas a smaller overlap was found between liver and pancreatic islets or adipose tissue, respectively. We identified 151 genes whose liver expression also correlated with age. We identified age-associated DNA methylation and expression changes in human liver that are partly reflected by epigenetic alterations in blood.
Highlights
Characteristics of liver donors To map the epigenome in human liver in relation to age, we analyzed DNA methylation of 455,526 CpG sites in liver biopsies of 95 individuals aged 28–64 years
In order to estimate the multicollinearity of the different phenotypes included in the linear regression model, we first calculated the Variance inflation factors (VIFs) for all these phenotypes
Methylation of CpG sites annotated to the gene ELOVL2 that, in our study, strongly correlated with age in human liver has previously been shown to display the widest methylation range along with age in whole blood [41] and white blood cells [12], suggesting that ELOVL2 could be a possible biomarker for epigenetic aging in human liver
Summary
Characteristics of liver donors To map the epigenome in human liver in relation to age, we analyzed DNA methylation of 455,526 CpG sites in liver biopsies of 95 individuals aged 28–64 years. When we compared the age-associated methylation data in pancreatic islets with the liver data, 120 sites were shared between the two tissues (Figure 3 & Supplementary Table 7) These include CpG sites annotated to the genes ELOVL2, KLF14 and FHL2. Pathway analysis of genes annotated to age-associated CpG sites shared by liver, blood and adipose tissue found enrichments of neuroactive ligand interaction, calcium signaling pathways, cancer pathways, mature onset diabetes on young, among others (Figure 5C). Validation of DNA methylation changes by pyrosequencing For validation of the Illumina 450K array data in liver, we performed pyrosequencing targeting four CpG sites of the genes KLF14 (cg14361627 and cg08097417) and FHL2 (cg06639320 and cg24079702), with significant age-associated methylation changes in human liver (Supplementary Table 2 & Figure 6A–D). The pyrosequencing data validated the array data and age-association for three of the selected CpG sites (p < 0.05; Figure 6E–K), while a nominal positive correlation with age was found for cg24079702 (Figure 6L)
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