Fig. 1.

Crosstalk between metabolism and chromatin. Deposition and removal of chromatin marks is influenced by metabolites, which function as cofactors or substrates for the chromatin modification enzymes. First, NAD⁺ concentration and NAD⁺/NADH ratio regulate the activity of the sirtuin NAD⁺-dependent histone deacetylases (SIRT) and poly(ADP-ribose) polymerases (PARPs). These two enzymes are involved in DNA damage repair and replication as well as in the regulation of chromatin compaction and gene transcription in eukaryotes. Low ATP/AMP ratios can activate AMPK, a kinase that phosphorylates histones. Acetyl-CoA is a donor for HAT-mediated histone acetylation, and α-ketoglutarate (αKG) is a cofactor for histone demethylation by Jumonji C-domain-containing histone lysine demethylases (HDM). Finally, S-adenosylmethionine (SAM), which is synthesized from the amino acid methionine, is the substrate for histone and DNA methyltransferases (HMT and DMT, respectively). Under stress conditions energy consumption increases while energy production decreases. A decrease in the energy metabolite ATP and a higher NAD⁺/NADH ratio are expected to lead to increased AMPK and SIRT activities, respectively. Depletion of the citrate cycle intermediates acetyl-CoA, and αKG is likely to affect the acetylation and demethylation of histones