Identification of nutrient metabolites capable of altering the epigenetic status at specific loci

Abstract

Nutrients can influence cellular functions associated with physiological and pathological processes. Major energy sources in our body, such as glucose and amino acids, are decomposed, resynthesized via numerous synthetic pathways, and finally, metabolized into energy molecules (e.g., ATP) and metabolites involved in various molecular events such as gene expression. Our previous study demonstrates that a sugar metabolite, N‐acetyl mannosamine, when used as a supplement in the culture medium, can induce the differentiation of pluripotent stem cells into orexin neurons and activate the epigenetic status at the orexin‐coding gene locus. Thus, our observations suggest that some metabolites can change the fate of a cell by participating in epigenetic alterations at specific loci. However, there is insufficient information about the role of specific nutrients and their metabolites in altering the epigenetic status. In the present study, we aimed to screen for metabolites that function as epigenetic modulators. We supplemented the culture medium with 129 metabolites individually during the induction of neural differentiation from human iPS cells (hiPSCs). We investigated the epigenetic status at 40 loci of the neural peptide‐coding genes by ChIP‐qPCR, using a high‐throughput platform. Trimethylation of lysine 4 of histone H3 (H3K4me3) and histone O‐GlcNAcylation of serine 40 of H2A (H2AS40Gc) were used as active epigenetic markers. Metabolites 4 and 12 considerably altered the levels of H3K4me3 and H2AS40Gc, respectively, at the loci of most genes, except at those of genes encoding pan‐neural markers. Among them, metabolites produced via the kynurenine pathway (one of the tryptophan metabolic pathways) increased H3K4me3 and H2AS40Gc levels at multiple neural peptide‐encoding gene loci such as CART (cocaine‐and amphetamine‐regulated transcript) and OXT (oxytocin). The mRNA expression levels of these genes were also found to have increased following supplementation of the culture medium with metabolites of the kynurenine pathway. In other words, supplementation with these metabolites could effectively induce the differentiation of hiPSCs into CART‐ and OXT‐producing neurons. Collectively, we have identified metabolites that can alter the epigenetic status at specific loci. Our findings provide a better understanding of the use of nutrients or bioactive food components in modifying epigenetic mechanisms.Support or Funding InformationThis work was supported by Lotte Shigemitsu Prize.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.