Seale, Kirsten (2023) Quantifying the ageing methylome: a multi-tissue map in humans. PhD thesis, Victoria University.

Abstract

The epigenome is a dynamic system of chemical modifications that operate to control chromatin structure and regulate gene activity without altering the underlying DNA sequence. One of the most extensively studied epigenetic marks is DNA methylation (DNAm) that occurs at cytosine-guanine (‘CpG’) dinucleotides in the genome. The DNAm landscape (‘the methylome’) is extensively remodelled during ageing. Studies have described various features of the ageing methylome, including linear changes at individual CpGs (i.e. differential and variable methylation) and in the distribution of methylation over all CpGs (i.e. entropy). Current research efforts have contributed greatly to our understanding of the ageing methylome; however, we still do not know the full extent to which the methylome is altered with ageing, and whether differences exist between different tissues. As such, teasing apart the global changes in DNAm that accrue over time, quantifying differentially and variably methylated positions (DMPs and VMPs) and entropy, in various tissues, is needed to obtain a better understanding of the ageing methylome in its entirety. The overarching objective for this PhD project was to quantify the age-related changes in DNAm, including DMPs, VMPs and entropy, in six human tissues, building the largest, multi-tissue map of DNAm ageing in humans. First, we assembled an extensive database of 40,830 human methylomes from 113 datasets in six human tissues, including blood, brain, skin, adipose, buccal and muscle tissue. Then, using a sophisticated statistical pipeline, we conducted a large-scale, multi-tissue Epigenome-Wide Association Study (EWAS) meta-analysis of age to quantify the tissue-specific signatures of DMPs, VMPs and entropy. We also performed functional enrichment analyses to provide biological interpretation of our findings. In blood, we found that 47% of the CpGs we investigated are DMPs with two-thirds of them (66%) hypomethylated with age, and 37% are VMPs. Entropy increases with age, but only DMPs are driving this increase. The other tissues were variable in the identified age-related changes. Despite varying degrees of statistical power, we detected DMPs in all tissues, and there was no consistent pattern of hyper- vs hypomethylation. We only detected VMPs in blood, brain, saliva, and skin, but not in muscle or adipose tissue. We hypothesise that these age-related changes reflect the proliferative capacities of tissues across the lifespan. However, this comparison between tissues may be biased by differences in the substructures of the tissue cohorts and varying statistical power, which strongly impacted our ability to detect age-related changes. By breaking down the methylome into individual components, focusing on DMPs, VMPs and entropy, we obtained a deeper understanding of the ageing methylome in its entirety. This research therefore holds the potential to contribute significantly to the current body of knowledge, by painting a global picture of epigenetic ageing in humans.

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