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

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

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. xuwei_0706@fudan.edu.cn.
  • 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. xuwei_0706@fudan.edu.cn.
  • 8 The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China. xuwei_0706@fudan.edu.cn.
  • 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. zhaosm@fudan.edu.cn.
  • 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. zhaosm@fudan.edu.cn.
  • 11 Key Laboratory for Tibet Plateau Phytochemistry of Qinghai Province, College of Pharmacy, Qinghai University for Nationalities, Xining, China. zhaosm@fudan.edu.cn.
  • 12 Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China. zhaosm@fudan.edu.cn.
  • # Contributed equally.
PMID: 34140692 DOI: 10.1038/s42255-021-00405-8
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.

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