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CELL CYCLE

TiPpIng the balance in histone acetylation

Nature Metabolism volume 3, pages 729–731 (2021)Cite this article

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Nutrient availability and the cell cycle are known to affect chromatin accessibility. A fundamental question is which mechanisms are involved in connecting nutrient levels, the cell cycle and chromatin regulation. In this issue, Zhang et al. reveal a signalling cascade whereby nutrient-sensing mTORC1 activates the cell-cycle regulator CDK2, thus leading to nuclear translocation of the metabolic enzyme triosephosphate isomerase 1 (TPI1). In the nucleus, TPI1 alters the levels of acetate and global histone acetylation through the metabolite dihydroxyacetone phosphate.

Histone acetylation status directly affects chromatin condensation and gene expression regulation, DNA repair and DNA replication. This modification is regulated by the balanced activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs). HATs and HDACs have been shown to spatially reorganize during cell division1. Acetyl-CoA, the substrate of HATs, is produced locally in the nucleus by multiple metabolic enzymes. Nuclear pyruvate dehydrogenase (nPDC) has been shown to translocate to the nucleus from the mitochondria and to produce acetyl-CoA from pyruvate2. nPDC levels are cell-cycle dependent, and nPDC activity influences cell-cycle progression. ATP-citrate lyase, which generates acetyl-CoA from citrate, has also been shown to localize to both the cytosol and the nucleus3, and to regulate cell proliferation and DNA repair in the latter. Finally, acetyl-CoA can be produced from acetate by acyl-CoA synthetase 2 (ACSS2). Nuclear ACSS2 has been shown to be important during metabolic stress and memory formation in neurons through site-specific acetyl-CoA production and histone acetylation4. These nuclear-localizing metabolic enzymes highlight a link between metabolism and chromatin dynamics.

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Fig. 1: A novel signalling–metabolic–epigenetic axis.

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Authors and Affiliations

  1. Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA

    Lara Roach & Raul Mostoslavsky

  2. The Broad Institute of Harvard and MIT, Cambridge, MA, USA

    Raul Mostoslavsky

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  1. Lara Roach
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  2. Raul Mostoslavsky
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Correspondence to Raul Mostoslavsky.

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Roach, L., Mostoslavsky, R. TiPpIng the balance in histone acetylation. Nat Metab 3, 729–731 (2021). https://doi.org/10.1038/s42255-021-00396-6

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