The epigenetic and morphogenetic effects of molecular oxygen and its derived reactive species in development

The development of multicellular organisms involves the unpacking of a complex genetic program. Extensive characterization of discrete developmental steps has revealed the genetic program is controlled by an epigenetic state. Shifting the epigenome is a group of epigenetic enzymes that modify DNA and proteins to regulate cell type specific gene expression. While the role of these modifications in development has been established, the input(s) responsible for electing changes in the epigenetic state remains unknown. Development is also associated with dynamic changes in cellular metabolism, redox, free radical production, and oxygen availability. It has previously been postulated that these changes are causal in development by affecting gene expression. This suggests that oxygen is a morphogenic compound that impacts the removal of epigenetic marks. Likewise, metabolism and reactive oxygen species influence redox signaling through iron and glutathione to limit the availability of key epigenetic cofactors such as α-ketoglutarate, ascorbate, NAD⁺ and S-adenosylmethionine. Given the close relationship between these cofactors and epigenetic marks it seems likely that the two are linked. Here we describe how changing these inputs might affect the epigenetic state during development to drive gene expression. Combined, these cofactors and reactive oxygen species constitute the epigenetic landscape guiding cells along differing developmental paths.