Figure 2.

An integrative genomic model of the major genetic and environmental pathways influencing the human methylome. The total human methylome is represented in the middle grey box that may vary in its overall level of saturation of DNA methylation. Four different categories of pathways that appear to influence saturation of DNA methylation are shown by the colored circles that are either creating supply or demand for methyl donors. Dietary inputs are required by SAM for DNA methylation in the one carbon cycle, while the biochemically linked pathway of GSH synthesis acts as inhibitors of SAM, creating a demand for more dietary inputs when chemicals are present and oxidative stress pathways are activated. Environmental toxins may also act directly as mutagens on the genome that may create more genome instability and potentially more CNV duplication events, creating more demand by increasing the size of the sink and could be self-perpetuating through hypomethylation. Lastly, viral infections or general inflammatory pathways may also increase demand on the need for methylation by promoting increased cell division, repression of viral DNA and DNA repair pathways.