Research interest:
Di Zhang's lab is dedicated to investigate new regulatory pathways of cellular metabolism regulating chromatin activity and how their abnormalities lead to human diseases such as tumors, autoimmune diseases and aging. Their major contributions in this area include:
Identification of a new histone modification driven by L-lactate, lysine lactylation; Identification of a new histone modification driven by ketone body, lysine β-hydroxybutyrylation. These metabolite-driven histone marks link gene transcription and cellular metabolism to adapt the cellular response to environmental changes.
Research Progress:
Class I histone deacetylases (HDAC1–3) are histone lysine delactylases
Lactate is an end product of the cellular glycolytic pathway, and its biological function has received much attention due to the presence of the Warburg effect in tumor cells. In 2019, we reported for the first time in Nature that lactate modifies histones in a covalent binding manner (lysine lactylation modification), and that in the presence of the "writer" histone acetyltransferase p300, histone lactylation modification regulates immune macrophage polarization-related gene expression during activation . However, studies on the regulatory mechanisms of lactylation modification are still in the early stages, and the "eraser" of lactylation modification, i.e., the de-lactylase, is still unreported.
This study found that cell lysates can remove lactylation modifications from histone lysine ε-amino acids and that broad-spectrum HDAC inhibitors inhibit this activity (see below); in vitro experiments showed that the recombinant protein HDAC1-3 can undergo demulsification of p53 peptide 317-320 containing lactylation modifications; when histones extracted from cells were used as substrates it was found that HDAC1-3 and SIRT1-3 both caused the de-lactylation of the level of lactylation modifications on histones. Among them, HDAC3 was the most effective "eraser" of lactylation modification.
Further, in this study, the first systematic exploration of the "eraser" of lactylation modification was performed using fluorescently labeled peptides, recombinant HDACs, Hela cell lines, etc., which revealed the de-lactylation modification activity of class I HDACs (HDAC1-3), and further explored the effect of HDAC1-3 on cell These results have laid a solid theoretical foundation for the future discovery of the fine regulation of lactylation modifications.
Publication
*Equal contribution
*Equal contribution
1. Moreno-Yruela, C., Zhang, D*., Wei, W., Bæk, M., Liu, W., Gao, J., Danková, D., Nielsen, A. L., Bolding, J. E., Yang, L., Jameson, S. T., Wong, J., Olsen, C. A., & Zhao, Y. (2022). Class I histone deacetylases (HDAC1-3) are histone lysine delactylases. Sci Adv, 8(3), eabi6696.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. Goudarzi A*, Zhang D*, Huang H, Barral S, Kwon OK, Qi S, Tang Z, Buchou T, Vitte AL, He T, Cheng Z, Montellier E, Gaucher J, Curtet S, Debernardi A, Charbonnier G, Puthier D, Petosa C, Panne D, Rousseaux S, Roeder RG, Zhao Y‡, Khochbin S‡. (2016). Dynamic Competing Histone H4 K5K8 Acetylation and Butyrylation Are Hallmarks of Highly Active Gene Promoters. Mol Cell. 62(2): 169-80.
8. Zhang Y*, Zhang D*, Liang J, Yi X, Gui B, Yu W, Sun L, Yang X, Han X, Chen Z, Liu S, Si W, Yan R, Wang Y, Shang Y‡. (2016). Nucleation of DNA Repair Factors by FOXA1 Links DNA Demethylation to Transcriptional Pioneering. Nat Genet. 48 (9):1003-13.
9. Li L, Shi L, Yang S, Yan R, Zhang D, Yang J, He L, Li W, Yi X, Sun L, Liang J, Cheng Z, Shi L, Yu W, Shang Y‡. (2016). SIRT7 Is a Histone Desuccinylase that Functionally Links to Chromatin Compaction and Genome Stability. Nat Commun. 7:12235.
Metabolism
https://en.wikipedia.org/wiki/Metabolic_pathway; From wiki
Lactylation
Nature 574，575-580 (2019)