4.8 Article

Enzymatic transfer of acetate on histones from lysine reservoir sites to lysine activating sites

Journal

SCIENCE ADVANCES
Volume 8, Issue 3, Pages -

Publisher

AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abj5688

Keywords

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Funding

  1. NIH [RO1AA027202, P01AG031862, R01CA078831, R01AG055570, F31 CA247348-02, K99AA028577, P01CA196539, T32 GM-07229]
  2. Alzheimer's Association [AARF-19-618159]
  3. National Institute on Aging Intramural Research Program (NIA IRP), NIH [ZIA AG000679]

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This study reveals the regulation of histone acetylation by nuclear acetyl-CoA pools and suggests a local transfer of acetate occurs during gene activation. The yeast ortholog of ACSS2, Acs2, is recruited to chromatin during quiescence exit and is preferentially associated with the most up-regulated genes, indicating the important role of acetyl group transfer in gene activation.
Histone acetylation is governed by nuclear acetyl-CoA pools generated, in part, from local acetate by metabolic enzyme acetyl-CoA synthetase 2 (ACSS2). We hypothesize that during gene activation, a local transfer of intact acetate occurs via sequential action of epigenetic and metabolic enzymes. Using stable isotope labeling, we detect transfer between histone acetylation sites both in vitro using purified mammalian enzymes and in vivo using quiescence exit in Saccharomyces cerevisiae as a change-of-state model. We show that Acs2, the yeast ortholog of ACSS2, is recruited to chromatin during quiescence exit and observe dynamic histone acetylation changes proximal to Acs2 peaks. We find that Acs2 is preferentially associated with the most up-regulated genes, suggesting that acetyl group transfer plays an important role in gene activation. Overall, our data reveal direct transfer of acetate between histone lysine residues to facilitate rapid transcriptional induction, an exchange that may be critical during changes in nutrient availability.

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