Folate is an essential water-soluble vitamin occurring naturally in select foods as well as in the synthetic form (folic acid) used in supplements and in food fortification programs (1
). There are many critical cellular pathways dependent on folate as a 1-carbon source including DNA, RNA, and protein methylation as well as DNA synthesis and maintenance. Folate can be a limiting factor in all these reactions ().
Figure 1 Folic acid metabolism. This schematic shows the process by which folate/folic acid is used for DNA methylation. The MTHFR 677C→T variant reduces enzyme activity (175) and may help to divert the available methyl groups from the DNA methylation (more ...)
Epigenetics is the study of heritable changes in phenotype or gene expression that do not result from changes in the primary DNA sequence (4
). Recognized mechanisms of epigenetic regulation in mammals include DNA methylation, post-translational modification of histones, chromatin remodeling, microRNAs, and long noncoding RNAs (6
). These epigenetic regulatory mechanisms modulate chromatin structure and contribute to regulation of the major molecular processes in the nucleus including transcription, replication, repair, and RNA processing. DNA methylation is a covalent modification of genomic DNA that modifies gene expression and provides a mechanism for transmitting and perpetuating epigenetic information through DNA replication and cell division. The role of DNA methylation in cellular regulation has also provided the potential for a new paradigm of disease intervention and treatment. The development of various inhibitors of DNA methylation that alter methylation patterns within intact mammalian cells has led to the clinical use of some inhibitors in experimental therapies for human diseases such as hematological malignancies (8
) and myelodysplastic disorders (9
DNA methylation patterns are stable and are retained in purified genomic DNA; therefore, studies of DNA methylation are amenable to a wide variety of cell-free assays and technologies including DNA methylation analysis at single-nucleotide resolution, next-generation sequencing, and genome-wide methylation profiling (10
) (). Currently, new DNA sequencing technologies are beginning to provide novel insight into genome-wide patterns of DNA methylation (10
). Although high-resolution truly genome-wide studies have been limited to a very small sample size, a recent study described the DNA methylation level at 1505 individual sites (loci) in 808 genes in 1628 human genomic DNA samples (14
). Even this tremendous data set only covers a tiny portion of the genome in a limited number of samples. Despite these recent advances, a basic understanding of normal variation in genomic patterns of DNA methylation in humans across tissues, age, populations, disease, or environmental conditions (including dietary intakes) have not been well described. The methods needed to undertake these types of studies and the infrastructure to do these analyses are rapidly emerging (10
Representative list of commonly used methodologies for analyzing DNA methylation1
This review was written to provide the nutritional scientist with a synopsis of the mechanistic aspects of DNA methylation as a background for understanding the potential for the nutrient folate to affect these same molecular processes. Specifically, highlights of the following are covered: the roles and mechanisms of DNA methylation and demethylation; the mechanisms of gene silencing by DNA methylation; the function of DNA methlyation; reprogramming of DNA methylation patterns during development and differentiation; and the importance of changes in DNA methylation (hyper- and hypomethylation). Following this, the potential role of folate in the DNA methylation process and its assessment as a folate status biomarker and link to disease outcomes are covered: folate’s role in 1-carbon metabolism related to DNA methylation; low folate status and DNA methylation; background of DNA methylation, cancer, and folate; studies of cancer patients and folate status and global DNA methylation; studies of healthy adults and folate status; changes in DNA methylation in response to the environment and diet—the importance of the developmental timing of exposure; studies of folate in the fetus, infants, cord blood; and high folate and folic acid intake and DNA methylation. The review concludes with a focus on research issues including methodological considerations that are key in planning and interpreting research investigations related to assessing differences in DNA methylation in response to changes in folate status. Clearly there are many challenging research issues that need to be addressed to fill in the gaps in our knowledge related to the potential for folate to modulate DNA methylation and potentially have an impact on development and health maintenance.