Sorry for the delay.
What is cool about this paper is that the authors show that global histone aceylation is increased in human colon carcinoma cells grown in the presence of glucose and that this is dependent on the enzyme ATP-citrate lyase (ACL). ACL generates acetyl-CoA from citrate (remember the TCA cycle…how many times did we have to memorize that?) and acetyl-CoA has been shown previously in yeast to serve as the acetyl donor for histone acetyltransferases (HATs). In this paper, the authors also show that adipocyte differentiation, and the gene expression changes that occur, are dependent on ACL. This finding, in addition to previous knowledge that histone deacetylation (via NAD+-dependent Sirtuins) and demethylation (via 2-alpha ketoglutarate-dependent prolyl isomerases) are metabolically regulated, argue that our natural metabolism as well as what we eat influences gene expression through dynamic alterations in chromatin modifications.
If you recall, in p23 overexpressing cells there are increases in metabolically regulated chromatin modifying enzymes (not ACL, but an enzyme that generates acetyl-CoA from long chain fatty acids) and I also see increases histone acetylation at p23 sensitive genes.
ACL affects the overall level of acetyl-CoA and thus protein acetylation, yet only histone acetylation and specific genes are shown to be sensitive to its activity modulation. The implicated selective mechanism is important for understanding the coordination of nutrient metabolism and gene regulation. The availability of acetyl-CoA impacts more than acetylation, cholesterol biosynthesis also uses acetyl-CoA, making lipid-based signaling subject to ACL modulation as well. So, findings of this paper and others such as the one showing ACL inhibition resulted in suppression of tumor cell growth need to be explained by weaving all these metabolic and signaling pathways.
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