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.