Metabolic regulation of gene expression by histone lactylation

Di Zhang, Zhanyun Tang, He Huang, Guolin Zhou, Chang Cui, Yejing Weng, Wenchao Liu, Sunjoo Kim, Sangkyu Lee, Mathew Perez-Neut, Jun Ding, Daniel Czyz, Rong Hu, Zhen Ye, Maomao He, Y. George Zheng, Howard A. Shuman, Lunzhi Dai, Bing Ren, Robert G. Roeder, Lev Becker () and Yingming Zhao ()
Additional contact information
Di Zhang: The University of Chicago
Zhanyun Tang: The Rockefeller University
He Huang: The University of Chicago
Guolin Zhou: The University of Chicago
Chang Cui: The University of Chicago
Yejing Weng: The University of Chicago
Wenchao Liu: The University of Chicago
Sunjoo Kim: Kyungpook National University
Sangkyu Lee: Kyungpook National University
Mathew Perez-Neut: The University of Chicago
Jun Ding: The University of Chicago
Daniel Czyz: The University of Chicago
Rong Hu: University of California at San Diego
Zhen Ye: University of California at San Diego
Maomao He: University of Georgia
Y. George Zheng: University of Georgia
Howard A. Shuman: The University of Chicago
Lunzhi Dai: The University of Chicago
Bing Ren: University of California at San Diego
Robert G. Roeder: The Rockefeller University
Lev Becker: The University of Chicago
Yingming Zhao: The University of Chicago

Nature, 2019, vol. 574, issue 7779, 575-580

Abstract: Abstract The Warburg effect, which originally described increased production of lactate in cancer, is associated with diverse cellular processes such as angiogenesis, hypoxia, polarization of macrophages and activation of T cells. This phenomenon is intimately linked to several diseases including neoplasia, sepsis and autoimmune diseases1,2. Lactate, which is converted from pyruvate in tumour cells, is widely known as an energy source and metabolic by-product. However, its non-metabolic functions in physiology and disease remain unknown. Here we show that lactate-derived lactylation of histone lysine residues serves as an epigenetic modification that directly stimulates gene transcription from chromatin. We identify 28 lactylation sites on core histones in human and mouse cells. Hypoxia and bacterial challenges induce the production of lactate by glycolysis, and this acts as a precursor that stimulates histone lactylation. Using M1 macrophages that have been exposed to bacteria as a model system, we show that histone lactylation has different temporal dynamics from acetylation. In the late phase of M1 macrophage polarization, increased histone lactylation induces homeostatic genes that are involved in wound healing, including Arg1. Collectively, our results suggest that an endogenous ‘lactate clock’ in bacterially challenged M1 macrophages turns on gene expression to promote homeostasis. Histone lactylation thus represents an opportunity to improve our understanding of the functions of lactate and its role in diverse pathophysiological conditions, including infection and cancer.

Date: 2019
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DOI: 10.1038/s41586-019-1678-1

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