Reciprocal regulation of phosphatidylcholine synthesis and H3K36 methylation programs metabolic adaptation

Phospholipid biosynthesis plays a role in mediating membrane-to-histone communication that influences metabolic decisions. Upon nutrient deprivation, phospholipid methylation generates a starvation signal in the form of S-adenosylmethionine (SAM) depletion, leading to dynamic changes in histone methylation. Here we show that the SAM-responsive methylation of H3K36 is critical for metabolic adaptation to nutrient starvation in the budding yeast Saccharomyces cerevisiae. We find that mutants deficient in H3K36 methylation exhibit defects in membrane integrity and pyrimidine metabolism and lose viability quickly under starvation. Adjusting the synthesis of phospholipids potently rewires metabolic pathways for nucleotide synthesis and boosts the production of antioxidants, ameliorating the defects resulting from the loss of H3K36 methylation. We further demonstrate that H3K36 methylation reciprocally regulates phospholipid synthesis by influencing redox balance. Our study illustrates an adaptive mechanism whereby phospholipid synthesis entails a histone modification to reprogram metabolism for adaptation in a eukaryotic model organism.

Automated summary

Phospholipid biosynthesis mediates communication between membranes and histone, influencing metabolic decisions. In response to nutrient deprivation, phospholipid methylation generates a starvation signal by depleting S-adenosylmethionine (SAM), causing dynamic changes in histone methylation. Our study highlights the critical role of SAM-responsive methylation of H3K36 in metabolic adaptation to nutrient starvation in Saccharomyces cerevisiae. Deficiency in H3K36 methylation leads to defects in membrane integrity and pyrimidine metabolism, and reduces viability under starvation. Modulating phospholipid synthesis effectively rewires metabolic pathways for nucleotide synthesis and enhances antioxidant production, improving the defects caused by loss of H3K36 methylation. Furthermore, we demonstrate that H3K36 methylation reciprocally regulates phospholipid synthesis by influencing redox balance. Our findings illustrate an adaptive mechanism in which phospholipid synthesis involves histone modification to reprogram metabolism for adaptation in a eukaryotic model organism.