Table 1.

Clock-regulated metabolites that participate in chromatin remodeling contribute to cellular differentiation prior to clock development

Metabolite	Metabolic pathway	Chromatin modification	Circadian interaction	Stem cell fate change
Acetyl-CoA	Glycolysis Tricarboxylic acid (TCA) cycle	Histone acetylation	Activity of acetyl-CoA synthetase 1 (AceCS1) requires cyclic acetylation dependent on a functional circadian clock and the NAD+-dependent deacetylase SIRT1 (Sahar et al. 2014). Catabolism of glucose to acetyl-CoA depends on ATP-citrate lyase (ACLY); ACLY protein levels are cyclic in the mouse liver (Mauvoisin et al. 2014).	Maintenance of pluripotency (Moussaieff et al. 2015)
α-Ketoglutarate	TCA cycle	Histone demethylation DNA demethylation	Inhibits JumonjiC domain–histone demethylase 1a (JARIDla), which associates with CLOCK:BMAL1 to facilitate Per2 transcription (DiTacchio et al. 2011).	Maintenance of pluripotency (Carey et al. 2015)
Nicotinamide adenine dinucleotide (NAD+)	Glycolysis	Histone deacetylation	In mouse liver, 24-hour cycling rhythm is exhibited (Krishnaiah et al. 2017). CLOCK:BMAL1 drives transcription of Nampt, a crucial enzyme for NAD+ production (Nakahata et al. 2009, Ramsey et al. 2009).	Acquisition and maintenance of pluripotency (Calvanese et al. 2010, Y. Lee et al. 2012, Lees et al. 2020, Tang et al. 2014)
S-adenosyl methionine (SAM)	One-carbon metabolism (SAM and methionine cycle)	Histone methylation DNA methylation	In mouse liver, 24-hour cycling rhythm is exhibited (Krishnaiah et al. 2017). Accumulation of SAM by-product SAH (S-adenosyl homocysteine) hinders transmethylation and elongates circadian period (Fustin et al. 2013).	Maintenance of pluripotency (Shiraki et al. 2014, Shyh-Chang et al. 2013)