Dietary micronutrient composition has long been recognized as a determining factor for human health. Historically, biochemical research has successfully unraveled how vitamins serve as essential cofactors for enzymatic reactions in the biochemical machinery of the cell. Folate, also known as vitamin B9, follows this paradigm as well. Folate deficiency is linked to adverse health conditions, and dietary supplementation with folate has proven highly beneficial in the prevention of neural tube defects. With its function in single-carbon metabolism, folate levels affect nucleotide synthesis, with implications for cell proliferation, DNA repair, and genomic stability. Furthermore, by providing the single-carbon moiety in the synthesis pathway for S-adenosylmethionine, the main methyl donor in the cell, folate also impacts methylation reactions. It is this capacity that extends the reach of folate functions into the realm of epigenetics and gene regulation. Methylation reactions play a major role for several modalities of the epigenome. The specific methylation status of histones, noncoding RNAs, transcription factors, or DNA represents a significant determinant for the transcriptional output of a cell. Proper folate status is therefore necessary for a broad range of biological functions that go beyond the biochemistry of folate. In this review, we examine evolutionary, genetic, and epigenomic footprints of folate and the implications for human health.
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