机构：[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]BK21 Plus KNU Multi-Omics based Creative Drug Research Team, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, South Korea.[4]Department of Microbiology, The University of Chicago, Chicago, IL, USA.[5]Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA.[6]Center for Epigenomics and Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA.[7]Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA, USA.[8]University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL, USA.[9]Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.[10]Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, China.四川大学华西医院[11]Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL, USA.
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.
基金：
University of Chicago, Nancy and Leonard Florsheim family
fund (Y.Z.), NIH grants R01GM115961, R01DK118266 (Y.Z.), R01DK102960, R01HL137998 (L.B.),
R01CA129325, R01DK071900 (R.G.R.), and NSF1808087 (Y.G.Z.).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2019]版：
大类|1 区综合性期刊
小类|1 区综合性期刊
最新[2023]版：
大类|1 区综合性期刊
小类|1 区综合性期刊
第一作者：
第一作者机构：[1]Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA.
共同第一作者：
通讯作者：
通讯机构：[1]Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA.[8]University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL, USA.[11]Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL, USA.
推荐引用方式(GB/T 7714)：
Di Zhang,Zhanyun Tang,He Huang,et al.Metabolic regulation of gene expression by histone lactylation.[J].Nature.2019,574(7779):575-580.doi:10.1038/s41586-019-1678-1.
APA：
Di Zhang,Zhanyun Tang,He Huang,Guolin Zhou,Chang Cui...&Yingming Zhao.(2019).Metabolic regulation of gene expression by histone lactylation..Nature,574,(7779)
MLA：
Di Zhang,et al."Metabolic regulation of gene expression by histone lactylation.".Nature 574..7779(2019):575-580
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