美国芝加哥大学Yingming Zhao和Lev Becker等研究人员发现，组蛋白乳酸化修饰能够调控基因表达。2019年10月24日出版的《自然》发表了这项成果。

研究人员发现组蛋白赖氨酸残基的乳酸来源的乳酸化作为表观遗传修饰，直接促进了染色质的基因转录。研究人员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。缺氧和细菌刺激通过糖酵解诱导乳酸的产生，并且其作为促进组蛋白乳酸化的前体。使用暴露于细菌的M1巨噬细胞作为模型系统，研究人员发现组蛋白乳酸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，组蛋白的乳酸化修饰增强，从而诱导涉及伤口愈合的稳态基因，包括Arg1。

总体而言，这些结果表明，细菌攻击的M1巨噬细胞中的内源性“乳酸时钟”打开基因表达以促进体内平衡。因此，组蛋白乳酸化提供了一个增进了解乳酸的功能及其在各种病理生理状况（包括感染和癌症）中作用的机会。

据介绍，瓦博格效应（最初用于描述癌症中乳酸生成的增加）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。这种现象与多种疾病密切相关，包括瘤形成、败血症和自身免疫疾病。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。

附：英文原文

Title: Metabolic regulation of gene expression by histone lactylation

Author: 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, Yingming Zhao

Issue&Volume: 2019-10-23

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.

DOI: 10.1038/s41586-019-1678-1

Source: https://www.nature.com/articles/s41586-019-1678-1