Influence of external factors on the human epigenome

Epigenetic mechanisms govern gene regulation and respond to both genetic and environmental influences. Epigenetic marks, including DNA methylation (DNAm) are dynamic across an individual’s life and may be influenced by several environmental and genetic factors. In this thesis, I evaluated several factors which influence the human epigenome using a bioinformatics approach. First, I explored the idea that DNAm changes may underlie the link between air pollution and poor health. I identified no significant link between background air pollution levels and DNAm, however, was able to identify a link between exposure to traffic related air pollution (TRAP) and DNAm. I identified 531 significant CpG sites related to TRAP which were enriched at regulatory sites and novel and previously reported transcription factor (TF) motifs and genes. Secondly, I explored the role of DNA methylation in autosomal sex differences. Specifically, I identified and validated 396 CpG sites and 266 differentially methylated regions associated with sex. We found the majority of these to be female-biased CpGs (74\%) and were enriched in CpG islands and located preferentially at 5/3’UTRs and enhancers. TF motif enrichment revealed enrichment of TF’s related to critical developmental processes and sex determination such as SRY and ESR1. Finally, I report a catalogue of loci across the human epigenome displaying either variable or stable inter- individual DNA methylation. I demonstrate that the majority of the VMPs are not controlled by age, sex or smoking status. I also report highly variable and stable CpG sites enriched at methylation sensitive TFs, highlighting that there is potentially a strong relationship between DNAm and TF binding, which will be important for gene regulation. In addition, I found that the VMPs were under higher genetic control than the SMPs and that this is in part directed by interindividual differences in 3D chromatin organisation. In summary, the results presented in this thesis give insights into the role that external factors play in influencing the human epigenome.