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Metabolic regulation of gene expression by histone lactylation

机译：组蛋白乳化作用对基因表达的代谢调控

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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.
机译：最初描述癌症中乳酸产生增加的Warburg效应与多种细胞过程有关，例如血管生成，缺氧，巨噬细胞极化和T细胞活化。这种现象与包括肿瘤，败血症和自身免疫性疾病在内的多种疾病密切相关（1,2）。乳酸从肿瘤细胞中的丙酮酸转化而来，是众所周知的能源和代谢副产物。然而，其在生理和疾病中的非代谢功能仍然未知。在这里，我们显示了组蛋白赖氨酸残基的乳酸衍生乳化作用作为表观遗传修饰，可直接刺激从染色质的基因转录。我们在人类和小鼠细胞的核心组蛋白上鉴定出28个乳酸化位点。缺氧和细菌挑战通过糖酵解诱导乳酸的产生，并且其作为刺激组蛋白乳化的前体。使用已暴露于细菌的M1巨噬细胞作为模型系统，我们显示出组蛋白乳化与乙酰化具有不同的时间动态。在M1巨噬细胞极化的后期，组蛋白的乳酸化作用增强，可诱导涉及伤口愈合的稳态基因，包括Arg1。总体而言，我们的结果表明，细菌攻击的M1巨噬细胞中的内源性“乳酸钟”开启了基因表达以促进体内平衡。因此，组蛋白乳酸化代表了一个机会，可以增进我们对乳酸的功能及其在各种病理生理状况（包括感染和癌症）中的作用的了解。

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  • 来源
    《Nature》 |2019年第7779期|575-580|共6页
  • 作者

    Zhang Di; Tang Zhanyun; Huang He; Zhou Guolin; Cui Chang; Weng Yejing; Liu Wenchao; Kim Sunjoo; Lee Sangkyu; Perez-Neut Mathew; Ding Jun; Czyz Daniel; Hu Rong; Ye Zhen; He Maomao; Zheng Y. George; Shuman Howard A.; Dai Lunzhi; Ren Bing; Roeder Robert G.; Becker Lev; Zhao Yingming;

  • 作者单位

    Univ Chicago Ben May Dept Canc Res Chicago IL 60637 USA;

    Rockefeller Univ Lab Biochem & Mol Biol 1230 York Ave New York NY 10021 USA;

    Univ Chicago Ben May Dept Canc Res Chicago IL 60637 USA|Chinese Acad Sci Shanghai Inst Mat Med Shanghai Peoples R China;

    Kyungpook Natl Univ Pharmaceut Sci Res Inst Coll Pharm BK21 Plus KNU Multiom Based Creat Drug Res Team Daegu South Korea;

    Univ Chicago Dept Microbiol Chicago IL 60637 USA;

    Univ Calif San Diego Ludwig Inst Canc Res La Jolla CA 92093 USA|Univ Calif San Diego Sch Med Ctr Epigen La Jolla CA 92093 USA|Univ Calif San Diego Sch Med Dept Cellular & Mol Med La Jolla CA 92093 USA;

    Univ Georgia Dept Pharmaceut & Biomed Sci Athens GA 30602 USA;

    Univ Chicago Ben May Dept Canc Res Chicago IL 60637 USA|Sichuan Univ West China Hosp Dept Gen Practice State Key Lab Biotherapy Chengdu Sichuan Peoples R China|Collaborat Innovat Ctr Biotherapy Chengdu Sichuan Peoples R China;

    Univ Chicago Ben May Dept Canc Res Chicago IL 60637 USA|Univ Chicago Med Ctr Comprehens Canc Chicago IL 60637 USA|Univ Chicago Ludwig Ctr Metastasis Res Chicago IL 60637 USA;

    Univ Chicago Ben May Dept Canc Res Chicago IL 60637 USA|Univ Chicago Med Ctr Comprehens Canc Chicago IL 60637 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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