Interaction between γ-radiation and dietary folate starvation metabolically reprograms global hepatic histone H3 methylation at lysine 4 and lysine 27 residues

The objective of the present study was to investigate the regulatory control of histone H3 methylation at lysine 4 (H3K4) and lysine 27 (H3K27) residues in response to the effect of folate deficiency and gamma (γ)-radiation. Male Swiss mice maintained on folate sufficient diet (FSD) and folate free diet (FFD) based on AIN-93M formula, were subjected to 2-4 Gy total body γ-irradiation. There was a significant decrease in liver folate levels with concomitant depletion of S-adenosylmethionine (SAM) reserves. Folate deficiency and γ-radiation together induced H3K4 histone methyltransferase (H3K4HMTase) and suppressed H3K27 histone methyltransferase (H3K27HMTase) activities in a dose and time dependent manner. Our studies suggested radiation induced metabolic reprogramming of H3K4/H3K27 methylation patterns in FFD animals. We showed that radiation toxicity diverted one-carbon (C1) flux in FFD fed animals towards H3K4 methylation. Present work on methylation pattern of histone lysine residues gains particular importance as methylation of H3K4 residues is associated with euchromatin while methylated H3K27 residues promote gene silencing. In conclusion, our study suggests that maintenance of genomic histone methylation under γ-radiation stress might be a very dynamic, progressive process that could be modulated by dietary folate deficiency leading to formation of epigenetically reprogrammed cells.

► Dietary folate alters histone H3 methylation at lysine residue after irradiation. ► Folate deficiency modulates liver methyl donor metabolite S-adenosylmethionine. ► It influences key enzymes directing one-carbon flux towards histone methylation. ► Dietary folate intake might protect from gamma (γ)-radiation induced toxicity.