The one carbon cycle encompasses the folate and methionine cycles to produce one carbon units for a variety of cellular processes. The methionine cycle, in particular, generates S-adenosylmethionine (SAM) from methionine, an essential amino acid. SAM is utilized by histone methyltransferases (HMTs) to methylate histone proteins. Histone methylation plays diverse roles in the establishment of chromatin states and the regulation of gene expression. Histones are methylated by histone methyltransferases (HMTs) and demethylated by histone demethylases (HDMs) the activities of which rely on molecules generated via cell metabolism, such as S-adenosylmethionine (SAM). It has been shown in vitro, physiological concentrations of SAM are close to reported Km values for histone methyltransferase enzymes. Therefore, histone methyltransferase activity is sensitive to small changes in intracellular concentrations of SAM that could arise from differences in nutrient availability.
Histone methylation has only recently been appreciated as a dynamic epigenetic mark. Of the numerous histone methylation modifications that occur, the importance of H3 lysine 4 trimethylation (H3K4me3), H3K9me3, and H3K27me3 in establishing and maintaining chromatin states and their influence on gene expression are well documented. To better define the relationship between SAM availability, histone methylation and downstream consequences on gene expression, I characterized the metabolic response to methionine restriction using metabolomic, transcriptomic, and epigenomic approaches. Together, we found a specific response to methionine deprivation lead to decreases in SAM and H3K4me3 providing a link between cell metabolism and epigenetics. We took this one step further, and analyzed the transcriptional response to methionine restriction to determine the effect of metabolic alterations in H3K4me3 on gene expression.
This work provides evidence for a link between metabolic status and histone methylation in cells that could give rise to changes in gene expression-whether transient or permanent-providing a molecular basis for how environmental factors, such as diet, can influence gene expression via cell metabolism.