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. Author manuscript; available in PMC: 2022 Mar 4.
Published in final edited form as: Cell Stem Cell. 2021 Mar 4;28(3):394–408. doi: 10.1016/j.stem.2021.02.011

Figure 4: TCA cycle metabolites and NAD+/NADH ratio regulate stem cell fate and function through chromatin modifications.

Figure 4:

Citrate derived acetyl-CoA is a substrate for histone acetyltransferase (HAT). Sirtuins, which are NAD+ dependent histone deacetylases, can remove histone acetyl marks. Mitochondria is a key regulator of the cellular NAD+/NADH ratio that regulates the activities of sirtuins. Similarly, mitochondrial one-carbon metabolism (1CM) contributes to the production of S-adenosyl methionine (SAM), which is a substrate for histone and DNA methyltransferases (KMTs, and DNMTs, respectively). Also, Jumonji C domain-containing ten-eleven translocation (TET) enzymes involved in the reversal of cytosine methylation and histone demethylases (KDMs) require α-KG, and these enzymes can be competitively inhibited by succinate, fumarate, and L-2-HG.