Cell Cycle Control of Nuclear Metabolism Couples Phosphatidylinositol Signaling to Histone Methylation

ABSTRACT Progression through the cell cycle requires coordinated regulation of transcription, chromatin state, and cellular metabolism. While metabolic enzymes are known to localize the nucleus and influence chromatin states, how nuclear metabolism itself oscillates during the cell cycle remains unexplored. Here, we combine a customized FUCCI‐3 reporter with chromatome mass spectrometry and high‐throughput imaging to systematically resolve nuclear and chromatin‐associated metabolic changes across cell cycle phases. We identify phosphatidylinositol metabolism as a nuclear pathway that oscillates with the cell cycle, with PIP5K1A, PLCD3, and PLD2 showing phase‐specific nuclear and chromatin dynamics. Nuclear PIP2 levels redistribute within the nucleus depending on cell cycle stage. Downregulation of PIP5K1A reduces nuclear PIP2 levels, whereas nuclear enrichment of PIP5K1A increases PIP2 abundance in the nucleus and nucleolus, functionally linking PIP5K1A nuclear localization to nuclear PIP2 synthesis. Moreover, perturbation of nuclear PIP2 synthesis alters chromatin methylation, with a pronounced impact on H4K20 monomethylation. Together, our results reveal that nuclear phosphatidylinositol metabolism is cell cycle regulated and functionally linked to chromatin methylation, establishing nuclear lipid metabolism as a previously unrecognized layer of cell cycle control.