Metabolic regulation of gene expression by histone lactylation
Authors: Robert G Roeder
Sangkyu Lee
He Huang
Daniel Czyz
Zhen Ye
Maomao He
Zhanyun Tang
Mathew Perez-Neut
Jun Ding
Guolin Zhou
Yejing Weng
Yingming Zhao
Bing Ren
Y George Zheng
Di Zhang
Howard A Shuman
Lunzhi Dai
Sunjoo Kim
Rong Hu
Chang Cui
Wenchao Liu
Lev Becker
Journal: Nature (2019)
Discipline: Multidisciplinary
Keywords: Warburg effect; lactate; histone lactylation; gene transcription; chromatin
Affiliations: Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA., Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY, USA., Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China., BK21 Plus KNU Multi-Omics based Creative Drug Research Team, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, South Korea., Department of Microbiology, The University of Chicago, Chicago, IL, USA., Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA., Center for Epigenomics and Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA., Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA, USA., Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, China., Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA. ., University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL, USA. ., Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL, USA. .

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. 

Retracted: No

PubPeer comments:
 The genes of lactate dehydrogenase A and B are located in different chromosomal locations, so knocking out LDHA can express LDHB , 
 Extended Data Fig. 3i shows expression of LDHB protein in HepG2 WT or LDHA- - cells. How is this possible in the complete absence of *Ldhb* mRNA transcripts? See [here, for example.] ![file] , 
 Readers should become aware of a preprint entitled Many Routes from Glycolysis to Histone PTMs. Nature u201cMatters Arisingu201d response to: Zhang et al. Metabolic regulation of gene expression by histone lactylation. (2019) Nature. 574(7779), 575-580. by Chaitanya A. Kulkarni and Paul Brookes which call into question part of the conclusions by Zhang et al., 2019 study The preprint was posted at: https: osf.io sba8j ,