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Chromatin as a key consumer in the metabolite economy

Abstract

In eukaryotes, chromatin remodeling and post-translational modifications (PTMs) shape the local chromatin landscape to establish permissive and repressive regions within the genome, orchestrating transcription, replication, and DNA repair in concert with other epigenetic mechanisms. Though cellular nutrient signaling encompasses a huge number of pathways, recent attention has turned to the hypothesis that the metabolic state of the cell is communicated to the genome through the type and concentration of metabolites in the nucleus that are cofactors for chromatin-modifying enzymes. Importantly, both epigenetic and metabolic dysregulation are hallmarks of a range of diseases, and this metabolism–chromatin axis may yield a well of new therapeutic targets. In this Perspective, we highlight emerging themes in the inter-regulation of the genome and metabolism via chromatin, including nonenzymatic histone modifications arising from chemically reactive metabolites, the expansion of PTM diversity from cofactor-promiscuous chromatin-modifying enzymes, and evidence for the existence and importance of subnucleocytoplasmic metabolite pools.

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Fig. 1: Metabolites regulate chromatin modifications.
Fig. 2: Nonenzymatic histone modifications.
Fig. 3: Metabolic pathways that produce and interconvert acyl-CoAs involved in histone acylations.
Fig. 4: Monoaminylation of histones.
Fig. 5: Spatial control of cellular acetyl-CoA. ACLY, ACSS2, and PDC use citrate, acetate, and pyruvate, respectively, to generate acetyl-CoA that is available for histone acetylation.
Fig. 6: Compartmentalized NAD+ synthesis coordinates glucose metabolism and transcription.

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Acknowledgements

We thank current and former members of the Muir laboratory for discussions and comments. Some of the work discussed herein was performed in the author’s laboratory and was supported by National Institutes of Health (NIH) Grants R37 GM086868, R01 GM107047 and P01 CA196539. K.L.D. was supported by an NIH Research Service Awards (5F32CA206418).

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Diehl, K.L., Muir, T.W. Chromatin as a key consumer in the metabolite economy. Nat Chem Biol 16, 620–629 (2020). https://doi.org/10.1038/s41589-020-0517-x

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