An epigenetic perspective on the free radical theory of development

Abstract

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.

Blood glutathione redox status and global methylation of peripheral blood mononuclear cell DNA in Bangladeshi adults

“…15 Under oxidizing conditions, cystathionine-β-synthase (CBS) activity increases to direct Hcys flux through the transsulfuration pathway for the generation of GSH. 16 Consequently, less Hcys is directed toward the regeneration of methionine, which may result in decreased SAM levels.…”

Epigenetic Control of Prolyl and Asparaginyl Hydroxylases in Prostate Cancer

“…Unlike genetic mutations that accumulate in cancer, epigenetic modifications are reversible [20]. We hypothesized that if DNA methylation of the PHD3 gene was responsible for its reduced expression, a DNA methyltransferase inhibitor such as 5-Aza-29-deoxycytidine (5-Aza-dC) should induce its expression.…”

Perinatal programming and cardiomyocyte aging

“…Поэтому мощ-ность антиоксидантных систем защиты эмбриона весьма низка [51]. По мере развития плаценты до-ставка кислорода к плоду возрастает и одновременно увеличивается продукция активных соединений кис-лорода.…”

“…По мере развития плаценты до-ставка кислорода к плоду возрастает и одновременно увеличивается продукция активных соединений кис-лорода. Предполагается, что этот нормальный окси-дативный стресс работает как эпигенетический фак-тор, способствующий клеточной дифференциации [51,52]. Выполняя роль сигнальных молекул, актив-ные соединения кислорода индуцируют экспрессию некоторых клеточных генов (HIF1A, CREB1, NFKB1), участвующих в изменении чувствительности клетки к вариациям концентрации кислорода, дифферен-циации и пролиферации клеток [52,53].…”