Metabolic modulation of transcription: The role of one-carbon metabolism

While it is well known that expression levels of metabolic enzymes regulate the metabolic state of the cell, there is mounting evidence that the converse is also true, that metabolite levels themselves can modulate gene expression via epigenetic modifications and transcriptional regulation. Here we focus on the one-carbon metabolic pathway, which provides the essential building blocks of many classes of biomolecules, including purine nucleotides, thymidylate, serine, and methionine. We review the epigenetic roles of one-carbon metabolic enzymes and their associated metabolites and introduce an interactive computational resource that places enzyme essentiality in the context of metabolic pathway topology. Therefore, we briefly discuss examples of metabolic condensates and higher-order complexes of metabolic enzymes downstreamof one-carbon metabolism. We speculate that they may be required to the formation of transcriptional condensates and gene expression control. Finally, we discuss new ways to exploit metabolic pathway compartmentalization to selectively target these enzymes in cancer.

Automated summary

Expression levels of metabolic enzymes can regulate the metabolic state of the cell, and metabolite levels themselves can modulate gene expression via epigenetic modifications and transcriptional regulation. The one-carbon metabolic pathway plays a vital role in providing building blocks for biomolecules and has epigenetic effects. Metabolic condensates and enzyme complexes downstream of one-carbon metabolism may be involved in transcriptional condensates and gene expression control. Exploiting metabolic pathway compartmentalization can be a selective approach to targeting enzymes in cancer.