Spatiotemporal Control of Acetyl-CoA Metabolism in Chromatin Regulation

• Published in: Trends in biochemical sciences (Amsterdam. Regular ed.) 2018-01, Vol.43 (1), p.61-74
• Main Authors: Sivanand, Sharanya, Viney, Isabella, Wellen, Kathryn E.
• Format: Article
• Language: English
• Subjects: Acetyl Coenzyme A - metabolism; acetyl-CoA; acetylation; Animals; Cell Nucleus - genetics; Cell Nucleus - metabolism; Chromatin - genetics; Chromatin - metabolism; compartmentalization; Cytosol - metabolism; epigenetics; Humans; metabolism
• ISSN: 0968-0004; 1362-4326
• DOI: 10.1016/j.tibs.2017.11.004

The epigenome is sensitive to the availability of metabolites that serve as substrates of chromatin-modifying enzymes. Links between acetyl-CoA metabolism, histone acetylation, and gene regulation have been documented, although how specificity in gene regulation is achieved by a metabolite has been challenging to answer. Recent studies suggest that acetyl-CoA metabolism is tightly regulated both spatially and temporally to elicit responses to nutrient availability and signaling cues. Here we discuss evidence that acetyl-CoA production is differentially regulated in the nucleus and cytosol of mammalian cells. Recent findings indicate that acetyl-CoA availability for site-specific histone acetylation is influenced through post-translational modification of acetyl-CoA-producing enzymes, as well as through dynamic regulation of the nuclear localization and chromatin recruitment of these enzymes. Global levels of histone acetylation are responsive to acetyl-CoA abundance. Acetyl-CoA production has been shown to modulate transcriptional responses in various conditions and cell types, although the mechanisms underlying specificity of gene regulation by acetyl-CoA have been unclear. Despite the permeability of nuclear pores to acetyl-CoA, recent metabolic evidence suggests that nuclear and cytosolic pools of acetyl-CoA may be, in large part, functionally distinct. The acetyl-CoA-producing enzymes ATP-citrate lyase, acyl-CoA synthetase short-chain family member 2 (ACSS2), and the pyruvate dehydrogenase complex are present in the nucleus, and the nuclear accumulation of each of these enzymes is regulated by specific stimuli. Recent studies have found that ACSS2 is recruited to chromatin, where it facilitates local histone acetylation and gene regulation.