Histone Methylation Dynamics and Gene Regulation Occur through the Sensing of One-Carbon Metabolism

S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) link one-carbon metabolism to methylation status. However, it is unknown whether regulation of SAM and SAH by nutrient availability can be directly sensed to alter the kinetics of key histone methylation marks. We provide evidence that the status of methionine metabolism is sufficient to determine levels of histone methylation by modulating SAM and SAH. This dynamic interaction led to rapid changes in H3K4me3, altered gene transcription, provided feedback regulation to one-carbon metabolism, and could be fully recovered upon restoration of methionine. Modulation of methionine in diet led to changes in metabolism and histone methylation in the liver. In humans, methionine variability in fasting serum was commensurate with concentrations needed for these dynamics and could be partly explained by diet. Together these findings demonstrate that flux through methionine metabolism and the sensing of methionine availability may allow direct communication to the chromatin state in cells. [Display omitted] •Histone methylation dynamics occur in response to changes in SAM and SAH•Metabolism-regulated histone methylation affects gene expression•Diet alters methionine metabolism and histone methylation in the liver•Variation in human serum MET occurs at levels needed to alter histone methylation Mentch et al. show that modulation of methionine metabolism, by altering nutrient availability, regulates SAM and SAH levels to drive specific histone methylation events that affect gene expression. Methionine cycle alterations can be sustained by diet in vivo and modulate histone methylation in the liver.