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Trends Biochem Sci. 2016 Aug;41(8):712-730. doi: 10.1016/j.tibs.2016.05.013. Epub 2016 Jun 23.

Metabolic Enzymes Moonlighting in the Nucleus: Metabolic Regulation of Gene Transcription.

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Department of Medicine, University of Alberta, Edmonton, AB T6G 2B7, Canada.
Department of Medicine, University of Alberta, Edmonton, AB T6G 2B7, Canada. Electronic address:


During evolution, cells acquired the ability to sense and adapt to varying environmental conditions, particularly in terms of fuel supply. Adaptation to fuel availability is crucial for major cell decisions and requires metabolic alterations and differential gene expression that are often epigenetically driven. A new mechanistic link between metabolic flux and regulation of gene expression is through moonlighting of metabolic enzymes in the nucleus. This facilitates delivery of membrane-impermeable or unstable metabolites to the nucleus, including key substrates for epigenetic mechanisms such as acetyl-CoA which is used in histone acetylation. This metabolism-epigenetics axis facilitates adaptation to a changing environment in normal (e.g., development, stem cell differentiation) and disease states (e.g., cancer), providing a potential novel therapeutic target.


epigenetic regulation; fuel and nutrient sensing; metabolic enzymes; nuclear translocation

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