A Chemogenetic System for Spatiotemporal Perturbation of Cellular Methylation Potential.

We developed a genetically encoded system to perturb the methylation potential of living cells by exploiting the metabolic consumption of S-adenosylmethionine (SAM) through a plant methyltransferase, eugenol O-methyltransferase 1 (EOMT1). This system enables control of intracellular SAM levels with spatio- and temporal precision, regulated by the expression of EOMT1 and the timing of eugenol addition. EOMT1 expression allowed concentration-dependent reduction of SAM levels within 30 min. The system revealed distinct histone marks such as H3K4me3, H3K9me3, and H3K27me3, which responded differentially to SAM perturbation, revealing variable sensitivity between histone methyltransferases and demethylases. In addition, the spatially restricted expression of EOMT1 enabled the metabolic link of SAM between multiple organelles.