Di Zhang
Email：zhangdi（at）pku.edu.cn
Lab Homepage：http://www.bio.pku.edu.cn/homes/Index/news_cont_jl/17/1080.html
Research Area
Metabolism not only provides cells with energy and biosynthetic building blocks but also functions as a critical regulatory system that shapes cellular behaviors through diverse mechanisms, thereby connecting metabolism to virtually all aspects of life processes. Our research team is dedicated to uncovering how metabolic signals regulate fundamental cellular activities through complex molecular mechanisms, enabling cells to adapt to dynamic environments. We further investigate how dysregulated metabolic pathways contribute to the initiation and progression of major human diseases.
By integrating classical biochemical, cellular, and molecular biology approaches with advanced multi-omics technologies, we have identified and characterized a series of metabolite-driven protein modifications, including lysine lactylation (mediated by lactate) and lysine β-hydroxybutyrylation (mediated by ketone bodies), revealing new mechanisms by which metabolism directly regulates cellular functions.
Specifically, our research focuses on:
Signal-regulatory functions of metabolites
— including metabolite-driven post-translational modifications and metabolite-mediated allosteric regulation.
Regulatory functions of metabolic enzymes beyond metabolism
— exploring how metabolic enzymes act as signaling molecules to control cellular behaviors.
Metabolic adaptation and novel mechanisms of metabolic regulation
— elucidating how cells adapt to metabolic changes and how these regulatory mechanisms contribute to physiology and disease.
Selected Publications:
(*Co-first author, # Corresponding author)
(1) Ren H, Tang Y, Zhang D#. (2025).The emerging role of protein l-lactylation in metabolic regulation and cell signalling. Nat Metab 7: 647–664.
(2) Zhang D#, Gao J, Zhu Z, Mao Q, Xu Z, Singh PK, Rimayi CC, Moreno-Yruela C, Xu S, Li G, Sin YC, Chen Y, Olsen CA, Snyder NW, Dai L, Li L, Zhao Y. (2025). Lysine L-lactylation is the dominant lactylation isomer induced by glycolysis. Nat Chem Biol. 21(1): 91–99.
(3) Ren H, Zhang D#. (2024). Lactylation constrains OXPHOS under hypoxia. Cell Res. 34(2): 91-92.
(4) Gao J, Sheng X, Du J, Zhang D, Han C, Chen Y, Wang C, Zhao Y. (2023). Identification of 113 new histone marks by CHiMA, a tailored database search strategy. Sci Adv. 9(14): eadf1416.
(5) Moreno-Yruela C, Zhang D*, Wei W, Bæk M, Liu W, Gao J, Danková D, Nielsen AL, Bolding JE, Yang L, Jameson ST, Wong J, Olsen CA, Zhao Y. (2022). Class I histone deacetylases (HDAC1-3) are histone lysine delactylases. Sci Adv. 8(3): eabi6696.
(6) Huang H, Zhang D*, Weng Y, Delaney K, Tang Z, Yan C, Qi S, Peng C, Cole PA, Roeder RG, Zhao Y. (2021). The regulatory enzymes and protein substrates for the lysine β-hydroxybutyrylation pathway. Sci Adv. 7(9): eabe2771.
(7) Zhang D*, Tang Z*, Huang H, Zhou G, Cui C, Weng Y, Liu W, Kim S, Lee S, Perez-Neut M, Czyz D, Hu R, Ye Z, He M, Zheng YG, Shuman H, Ding J, Dai L, Ren B, Robert RG, Becker L, Zhao Y. (2019). Metabolic regulation of gene expression by histone lactylation. Nature. 574: 575-580.
(8) Huang H, Zhang D, Wang Y, Perez-Neut M, Han Z, Zheng YG, Hao Q, Zhao Y. (2018). Lysine benzoylation is a histone mark regulated by SIRT2. Nat Commun. 9(1): 3374.
(9) Sabari BR*, Zhang D*, Allis CD, Zhao Y. (2017). Metabolic Regulation of Gene Expression through Differential Histone Acylation. Nat Rev Mol Cell Biol. 18(2): 90-101.
(10) Xie Z*, Zhang D*, Chung D*, Tang Z, Huang H, Dai L, Qi S, Li J, Colak G, Chen Y, Xia C, Peng C, Ruan H, Kirkey M, Wang D, Jensen LM, Kwon OK, Lee S, Pletcher SD, Tan M, Lombard DB, White KP, Zhao H, Li J, Roeder RG, Yang X, Zhao Y. (2016). Metabolic Regulation of Gene Expression by Histone Lysine beta-hydroxybutyrylation. Mol Cell. 62(2): 194-206.
