Methyl-Metabolite Depletion Elicits Coordinated Responses to Support Heterochromatin Stability and Epigenetic Persistence

Abstract

S-adenosylmethionine (SAM) is the methyl-donor cofactor for the DNA and histone methyltransferases that regulate cellular epigenetic states; however, the adaptive mechanisms that allow cells to actively respond to – and recover their functional epigenomes from – perturbations in SAM availability are unknown. Here, we identify an evolutionarily conserved response to SAM depletion that is highlighted by preferential mono-methylation of H3 Lys 9 (H3K9me1) at the expense of global losses in histone di- and tri-methylation. These coordinated pathways drive de novo cytoplasmic and nuclear mono-methylation of H3K9 to preserve heterochromatin stability and support global epigenetic persistence upon metabolic recovery. Furthermore, the dynamic chromatin response at H3K9 to diet-induced SAM deficiency and subsequent metabolic recovery was robust in both young and old C57BL/6J mice, coinciding with whole animal changes in energy metabolism. Together, these studies are the first to reveal active mechanisms for epigenetic adaptation and persistence in response to metabolic stress.