Abstract
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 are 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 are currently hampered by a lack of data addressing the true biological significance and meaning of these small differences.Our 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.This review addresses the current pathophysiological and clinical associations of such characteristically small DNA methylation changes, the ever-growing roles of DNA methylation and the evidence available, particularly from the glucocorticoid receptor 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.
Highlights
Two clear methylation paradigms DNA methylation and hydroxyl-methylation are amongst the more intensely studied epigenetic mechanisms
We summarise the pathophysiological and clinical associations that have been made to small, subtle methylation changes; the ever-growing roles of DNA methylation; and the evidence available, from the glucocorticoid receptor of the cascade of events initiated by such subtle methylation changes, and conclude that such small changes may reflect genuine biological differences
The two definitions can be compared to strict Boolean or fuzzy logic. This definition is amenable to the integration of data, such as ours, from the epigenetic regulation of the NR3C1, as it would appear that a combination of genetic and epigenetic variants underpin and orchestrate the higgledy-piggledy or fuzzy processes into a concerted, specific response to the external environment
Summary
Two clear methylation paradigms DNA methylation and hydroxyl-methylation are amongst the more intensely studied epigenetic mechanisms. For both tissue-specific regulation and non-malignant disorders, changes in gene expression are frequently caused by small changes in methylation levels, often at single CpG dinucleotides or over a limited genomic region Such small differences have a big impact on the phenotype diversity that is linked to the onset of non-malignant diseases [15, 17]. Wilcoxd at test, paired t test bWilcox, Wilcoxon signed-rank test ct test, two-sample t test dWilcox, Wilcoxon rank-sum test identified biological and environmental risk factors, it is unlikely to have a single underlying cause, and the methylation changes identified may represent a ‘final common pathway’ [100] integrating many potential pathways This highlights that differentially methylated regions are not exclusively biomarkers as they are often reported, but may provide significant insight into the underlying mechanisms. At the population level, methylation clusters appeared to behave in a manner similar to genetic variants with multiple clusters of methylation in ‘linkage-disequilibrium’ covering distances up to 300 kbp [107]
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