Nuclear dihydroxyacetone phosphate signals nutrient sufficiency and cell cycle phase to global histone acetylation PMID: 34140692

ADC Targets in Oncology

2026-04-10

Nuclear dihydroxyacetone phosphate signals nutrient sufficiency and cell cycle phase to global histone acetylation

Nat Metab. 2021 Jun;3(6):859-875. doi: 10.1038/s42255-021-00405-8.

Jiao-Jiao Zhang ^# ¹ ² , Ting-Ting Fan ^# ¹ , Yun-Zi Mao ^# ¹ , Jun-Li Hou ³ , Meng Wang ¹ ⁴ , Min Zhang ³ , Yan Lin ¹ ² , Lei Zhang ¹ , Guo-Quan Yan ¹ , Yan-Peng An ¹ , Jun Yao ¹ , Cheng Zhang ¹ , Peng-Cheng Lin ⁵ , Yi-Yuan Yuan ¹ ² , Jian-Yuan Zhao ¹ ² , Wei Xu ⁶ ⁷ ⁸ , Shi-Min Zhao ⁹ ¹⁰ ¹¹ ¹²

Affiliations

1. Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, Shanghai Key Laboratory of Metabolic Remodeling, School of Life Sciences and Institutes of Biomedical Sciences, Shanghai, China.
2. NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Institute of Metabolism and Integrative Biology and Children's Hospital of Fudan University, Shanghai, China.
3. Department of Chemistry, Fudan University, Shanghai, China.
4. The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China.
5. Key Laboratory for Tibet Plateau Phytochemistry of Qinghai Province, College of Pharmacy, Qinghai University for Nationalities, Xining, China.
6. Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, Shanghai Key Laboratory of Metabolic Remodeling, School of Life Sciences and Institutes of Biomedical Sciences, Shanghai, China. [email protected].
7. NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Institute of Metabolism and Integrative Biology and Children's Hospital of Fudan University, Shanghai, China. [email protected].
8. The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China. [email protected].
9. Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, Shanghai Key Laboratory of Metabolic Remodeling, School of Life Sciences and Institutes of Biomedical Sciences, Shanghai, China. [email protected].
10. NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Institute of Metabolism and Integrative Biology and Children's Hospital of Fudan University, Shanghai, China. [email protected].
11. Key Laboratory for Tibet Plateau Phytochemistry of Qinghai Province, College of Pharmacy, Qinghai University for Nationalities, Xining, China. [email protected].
12. Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China. [email protected].
# Contributed equally.

Abstract

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.