Abstract
Epigenetic modifications are responsible for finetuning gene expression profiles to the needs of cells, tissues, and organisms. To rapidly respond to environmental changes, the activity of chromatin modifiers critically depends on the concentration of a handful of metabolites that act as substrates and co-factors. In this way, these enzymes act as metabolic sensors that directly link gene expression to metabolic states. Although metabolites can easily diffuse through the nuclear pore, molecular mechanisms must be in place to regulate epigenetic marker deposition in specific nuclear subdomains or even on single loci. In this review, I explore the possible subcellular sites of metabolite production that influence the epigenome. From the relationship between cytoplasmic metabolism and nuclear metabolite deposition, I converse to the description of a compartmentalized nuclear metabolism. Last, I elaborate on the possibility of metabolic enzymes to operate in phase-separated nuclear microdomains formed by multienzyme and chromatin-bound protein complexes.
Highlights
In the last 2 decades, the field of epigenomics has identified an immense variety of chromatin modifiers that collaborate to establish the epigenetic code
Cellular metabolism is the cluster of enzymatic reactions that occur in cells to transform nutrients such as glucose, fatty acids, amino acids, and vitamins into cellular components, energy, and reducing power
It is unlikely that passive diffusion of metabolites from the cytoplasm into the nucleus forms the basis of the metabolismepigenetic link
Summary
In the last 2 decades, the field of epigenomics has identified an immense variety of chromatin modifiers that collaborate to establish the epigenetic code. In the hepatic cell line HepG2, H3K9 acetylation of promoters involved in xenobiotic metabolism was regulated through the local activity of both PKM2 and the PDC, together responsible for shuttling glucose intermediates into nuclear acetyl-CoA pools In this case, PKM2 and the PDC were directed to specific promoters by forming a complex with the transcription factor Aryl-hydrocarbon receptor (AhR) (Matsuda et al, 2016) (Figure 3). In yeast, enzymes responsible for the local production of ATP, SAMe, and acetyl-CoA (Pyk, SAM synthetases, and an acetyl-CoA synthetase, respectively) were found to form a large chromatin-bound complex termed SESAME This complex balances glucose availability with glycolytic flux through the combined modulation of SAM and ATP availability for H3K4 methylation and H3T11 phosphorylation on histones of the promoter of the yeast PKM2 homolog Pyk (Li et al, 2015). It remains to be seen whether metabolic complexes lie at the heart of epigenetic condensates, and whether mechanisms exist to control the import or exclusion of metabolic pathways within these droplets
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