Accumulation of S-adenosyl-L-homocysteine impairs methylation and development in Saccharomyces cerevisiae and Drosophila melanogaster

S -adenosyl- L -homocysteine (SAH), the product inhibitor of S -adenosyl- L -methionine (SAM)-dependent methyltransferases, and its degradation product homocysteine (Hcy) are evolutionarily conserved master regulators of methylation metabolism. They can affect more than 200 methyltransferases in humans interfering with numerous methylation-dependent processes. Hyperhomocysteinemia (HHcy), characterized by elevated Hcy levels in the blood, is an independent risk factor for atherosclerosis and a strong predictor of cardiovascular mortality, yet, the mechanisms by which elevated Hcy contributes to pathological consequences remain poorly understood. Here we developed a Drosophila dietary HHcy model, as well as a genetic SAH hydrolase (SAHH) in vivo knockdown model and compared them to corresponding yeast models to reveal evolutionarily conserved developmental effects and methylation pattern changes. Feeding Drosophila a Hcy-containing diet or growing yeast on Hcy-supplemented medium similarly to genetically blocking SAH degradation leads to SAH accumulation, developmental delay and growth defects. Furthermore, Hcy supplementation or genetically induced SAH accumulation leads to impaired protein and phospholipid (PL) methylation in both model organisms. While total protein arginine methylation is significantly decreased in wild type yeast grown in presence of Hcy or in the ∆ sah1 yeast mutant, it is unaffected in Drosophila larvae raised on Hcy-supplemented diet. In contrast, histone methylation is affected in Drosophila and yeast, but exhibited differences in responses of particular histone methylation sites. Similarly, PL methylation was reduced in both organisms and resulted in deregulation of lysoPL metabolism suggesting PL remodeling. Functional characterization of evolutionary conserved Hcy/SAH-dependent methylation targets in Drosophila and yeast will reveal mechanisms of SAH toxicity which may be operative in HHcy-associated human pathologies.