Metabolic regulation of gene expression by histone lactylation

Nature. 2019 Oct;574(7779):575-580. doi: 10.1038/s41586-019-1678-1.

Di Zhang ^# ¹, Zhanyun Tang ^# ², He Huang ¹ ³, Guolin Zhou ¹, Chang Cui ¹, Yejing Weng ¹, Wenchao Liu ¹, Sunjoo Kim ⁴, Sangkyu Lee ⁴, Mathew Perez-Neut ¹, Jun Ding ¹, Daniel Czyz ⁵, Rong Hu ⁶ ⁷, Zhen Ye ⁶ ⁷, Maomao He ⁸, Y George Zheng ⁸, Howard A Shuman ⁵, Lunzhi Dai ¹ ⁹, Bing Ren ⁶ ⁷, Robert G Roeder ², Lev Becker ¹⁰ ¹¹ ¹², Yingming Zhao ¹³ ¹⁴

Affiliations

1 Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA.
2 Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY, USA.
3 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
4 BK21 Plus KNU Multi-Omics based Creative Drug Research Team, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, South Korea.
5 Department of Microbiology, The University of Chicago, Chicago, IL, USA.
6 Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA.
7 Center for Epigenomics and Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA.
8 Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA, USA.
9 Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, China.
10 Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA. levb@uchicago.edu.
11 University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL, USA. levb@uchicago.edu.
12 Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL, USA. levb@uchicago.edu.
13 Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA. yingming.zhao@uchicago.edu.
14 University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL, USA. yingming.zhao@uchicago.edu.
# Contributed equally.

PMID: 31645732 DOI: 10.1038/s41586-019-1678-1

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 diseases^1,2. 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.

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