Journal
NATURE METABOLISM
Volume 3, Issue 6, Pages 859-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s42255-021-00405-8
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Funding
- State Key Development Programs of China [2018YFA0801300, 2018YFA0800300, 2018YFC1004700, 2019YFA0801900, 2020YFA0803600]
- National Science Foundation of China [31821002, 31930062, 91857000]
- Shanghai Rising-Star Program [18QA1400300]
- Medical and Health Commission of Shanghai [2018YQ36]
- Key Laboratory of Reproduction Regulation of NHC [CX2017-0X]
- Key Laboratory of Reproduction Regulation of NPFPC
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The glycolytic enzyme TPI1 plays a crucial role in regulating nuclear acetate levels, which in turn affect global histone acetylation.
Zhang et al. identify a nuclear role for the glycolytic enzyme TPI1 in connecting nutrient status and cell cycle status to global histone acetylation. Global histone acetylation varies with changes in the nutrient and cell cycle phases; however, the mechanisms connecting these variations are not fully understood. Herein, we report that nutrient-related and cell-cycle-regulated nuclear acetate regulates global histone acetylation. Histone deacetylation-generated acetate accumulates in the nucleus and induces histone hyperacetylation. The nuclear acetate levels were controlled by glycolytic enzyme triosephosphate isomerase 1 (TPI1). Cyclin-dependent kinase 2 (CDK2), which is phosphorylated and activated by nutrient-activated mTORC1, phosphorylates TPI1 Ser 117 and promotes nuclear translocation of TPI1, decreases nuclear dihydroxyacetone phosphate (DHAP) and induces nuclear acetate accumulation because DHAP scavenges acetate via the formation of 1-acetyl-DHAP. CDK2 accumulates in the cytosol during the late G1/S phases. Inactivation or blockade of nuclear translocation of TPI1 abrogates nutrient-dependent and cell-cycle-dependent global histone acetylation, chromatin condensation, gene transcription and DNA replication. These results identify the mechanism of maintaining global histone acetylation by nutrient and cell cycle signals.
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