DNA methylation, through 5-methyl- and 5-hydroxymethylcytosine (5mC and 5hmC) is considered to be one of the principal interfaces between the genome and our environment and it helps explain phenotypic variations in human populations. Initial reports of large differences in methylation level in genomic regulatory regions, coupled with clear gene expression data in both imprinted genes and malignant diseases provided easily dissected molecular mechanisms for switching genes on or off. However, a more subtle process is becoming evident, where small (<10%) changes to intermediate methylation levels were associated with complex disease phenotypes. This has resulted in two clear methylation paradigms. The latter "subtle change" paradigm is rapidly becoming the epigenetic hallmark of complex disease phenotypes, although we were currently hampered by a lack of data addressing the true biological significance and meaning of these small differences. The initial expectation of rapidly identifying mechanisms linking environmental exposure to a disease phenotype led to numerous observational/association studies being performed. Although this expectation remains unmet, there is now a growing body of literature on specific genes, suggesting wide ranging transcriptional and translational consequences of such subtle methylation changes. Data from the glucocorticoid receptor (NR3C1) has shown that a complex interplay between DNA methylation, extensive 5"UTR splicing and microvariability gives rise to the overall level and relative distribution of total and N-terminal protein isoforms generated. Additionally, the presence of multiple AUG translation initiation codons throughout the complete, processed, mRNA enables translation variability, hereby enhancing the translational isoforms and the resulting protein isoform diversity; providing a clear link between small changes in DNA methylation and significant changes in protein isoforms and cellular locations. Methylation changes in the NR3C1 CpG island, alters the NR3C1 transcription and eventually protein isoforms in the tissues, resulting in subtle but visible physiological variability. Implying external environmental stimuli act through subtle methylation changes, with transcriptional microvariability as the underlying mechanism, to fine-tune the total NR3C1 protein levels. The ubiquitous distribution of genes with similar structure as NR3C1, combined with an increasing number of studies linking subtle methylation changes in specific genes with wide ranging transcriptional and translational consequences, suggested a more genome-wide spread of subtle DNA methylation changes and transcription variability. The subtle methylation paradigm and the biological relevance of such changes were supported by two epigenetic animal models, which linked small methylation changes to either psychopathological or immunological effects. The first model, rats subjected to maternal deprivation, showed long term behavioural and stress response changes. A second model, exposing mice to early life infection with H1N1, illustrated long-term immunological effects. Both models displayed subtle changes within the methylome. Suggesting/Indicating that early life adversity and early life viral infection "programmed" the CNS and innate immune response respectively, via subtle DNA methylation changes genome-wide. The research presented in this thesis investigated the ever-growing roles of DNA methylation; the physiological and functional relevance of subtle small DNA methylation changes genome-wide, in particular for the CNS (MD model) and the immune system (early life viral infection model) ; and the evidence available, particularly from the glucocorticoid of the cascade of events initiated by such subtle methylation changes, as well as addressing the underlying question as to what represents a genuine biologically significant difference in methylation.