Nature 574, 575–580 (2019)
The production of lactate modulates angiogenesis, hypoxia and immune cell function. In Nature, Zhao and colleagues show that lactate drives the lactylation of histone lysine residues and directly modulates gene transcription. In human HeLa cells and mouse bone marrow–derived macrophages (BMDMs), histone lysine lactylation (Kla) is driven by extracellular lactate or glucose-derived intracellular lactate and is increased during hypoxia, which increases glycolysis and the production of lactate. Histone Kla is induced with slower kinetics (24 h) than is histone acetylation (6 h). BMDMs treated with lipopolysaccharide and the cytokine IFN-γ or with Gram-negative bacteria have more H3K18la in the promoters of genes that are activated at later timepoints (24 h) and encode non-inflammatory, homeostatic mediators, such as Arg1. LPS- and IFN-γ-polarized BMDMs deficient in the lactate dehydrogenase LDHA have less production of lactate, less global histone Kla and lower expression of Arg1 than that of wild-type BMDMs, whereas their expression of pro-inflammatory cytokines is normal. In transcription assays, histone lactylation promotes gene transcription similar to histone acetylation.