An epigenetic perspective on the free radical theory of development

The development of organisms requires concerted changes in gene activity. The free radical theory of development proposes that oxygen serves as a morphogen to educe development by influencing the production of metabolic oxidants such as free radicals and reactive oxygen species. One of the central tenets of this theory is that these metabolic oxidants influence development by altering the antioxidant capacity of cells by changing their production of glutathione (GSH). Here we extend on these principles by linking GSH production and oxygen sensing in the control of gene expression to establish the epigenotype of cells during development. We prescribe this novel role to GSH and oxygen during development because these metabolites influence the activity of enzymes responsible for initiating and perpetuating epigenetic control of gene expression. Increased GSH production influences epigenetic processes including DNA and histone methylation by limiting the availability of S-adenosylmethionine, the cofactor utilized during epigenetic control of gene expression by DNA and histone methyltransferases. Moreover, the recent discovery of histone demethylases that require oxygen as a cofactor directly links epigenetic processes to oxygen gradients during development.