The molecular machinery that senses changes in the micro-environment of cells and translates them into epigenome modulations of DNA or histone tails, thereby influencing gene expression, is comprised of various kinases, acetyltransferases, and methyltransferases. These enzymes need appropriate levels of phosphate, acetyl, and methyl groups, respectively, to elicit these modifications (Lee and Workman 2007). As a result, chromatin-remodeling enzymes consume key metabolites such as SAM for methylation, ATP for phosphorylation, and acetyl-CoA, NAD+, NADH, and acetyl-ADP-ribose for acetylation. These enzymes differ significantly in their affinities for their cofactors, which together with fluctuations in the cofactors’ concentrations and their subcellular distribution (e.g., as a result of circadian rhythmicity, oxygen tension, or nutritional status) influence enzymes’ ability to perform their functions (Albaugh et al. 2011). At least two groups of chromatin regulators—the sirtuins that act as class III histone deacetylases and the poly-ADP ribose polymerases (PARPs)—depend on NAD+ levels, which are regulated in a circadian manner linked to energy metabolism (Nakahata et al. 2009). Many signaling pathways, such as Notch and TGFβ, in conjunction with downstream transcription factors, can express or recruit enzymes that modify chromatin (Mohammad and Baylin 2010).
