Regulation of acetyl‐CoA homeostasis and global histone acetylation (942.1)

Abstract

Acetyl‐CoA is a key metabolite at the crossroads of metabolism, signaling, chromatin structure, and transcription. Concentration of acetyl‐CoA affects histone acetylation and links intermediary metabolism and transcriptional regulation. We have identified acetyl‐CoA carboxylase, encoded in yeast by the ACC1 gene, as the key regulator of acetyl‐CoA homeostasis. Acc1p catalyzes the carboxylation of acetyl‐CoA to malonyl‐CoA, the first and rate‐limiting reaction in the de novo synthesis of fatty acids. Attenuated expression of ACC1 results in increased cellular level of acetyl‐CoA, increased histone acetylation and altered transcriptional regulation. The glucose sensor Snf1p, the yeast ortholog of the mammalian AMP‐activated protein kinase (AMPK), phosphorylates and inactivates Acc1p. Inactivation of Snf1p results in an increased conversion of acetyl‐CoA to malonyl‐CoA, reduced pool of cellular acetyl‐CoA, and globally decreased histone acetylation. Collectively, our results demonstrate that signaling pathways that affect acetyl‐CoA homeostasis regulate global histone acetylation and transcriptional regulation. Our current experiments test the hypothesis that global histone acetylation functions as a signal reflecting acetyl‐CoA homeostasis and metabolic state of the cell.Grant Funding Source: Supported by NIH