Nuclear metabolism oscillation during the cell cycle reveals a link between the phosphatidylinositol pathway and histone methylation.

The progression of the cell cycle is regulated by the expression of specific genes and fluctuations in cellular metabolic states. Previous research has employed cell cycle-based transcriptomics, proteomics, and metabolomics analyses to identify cell cycle-dependent changes at the gene expression, protein, and metabolic levels. However, the role of protein compartmentalization in regulating protein function, coupled with evidence that metabolic enzymes can localize to the nucleus and influence chromatin states, suggests that fluctuations in nuclear metabolism may play a role in regulating cell cycle progression. In this study, we developed an approach to resolve chromatin and nuclear changes during the cell cycle in an unbiased and systematic manner. This was achieved by integrating cell cycle fluorescent reporters with chromatin mass spectrometry and cellular imaging. Our investigation focused on metabolic enzymes and revealed that phosphatidylinositol metabolism localizes to the nucleus in a cell cycle-dependent manner. Moreover, disruption of phosphatidylinositol metabolism affects the nuclear distribution of phosphatidylinositol 4,5-bisphosphate, alters the number and morphology of nucleoli, and influences the maintenance of distinct heterochromatin states throughout the cell cycle. Finally, given the established link between phosphatidylinositol metabolism and methionine synthesis, as well as the differential impact observed on distinct histone marks when phosphatidylinositol metabolism is perturbed, we proposed that distinct pools of methionine may be involved in the maintenance of histone marks that decorate heterochromatin in a cell cycle-dependent manner.