Editors' ChoiceEpigenetics

Lactylation drives resolution

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Science Signaling  05 Nov 2019:
Vol. 12, Issue 606, eaba0502
DOI: 10.1126/scisignal.aba0502

Histone modifications derived from the metabolite lactate promote transcription of genes necessary for the resolution of inflammation.

Posttranslational modification of histone proteins can alter chromatin structure and gene expression. Histone phosphorylation, methylation, ubiquitylation, acetylation, citrullination, ADP ribosylation, propionylation, butyrylation, malonylation, succinylation, glutarylation, 2-hydroxyisobutyrylation, crotonylation, and serotonylation have all been described. Because a number of these modifications are due to the covalent attachment of metabolite-derived groups, Zhang et al. investigated whether histones could be modified by lactylation, the covalent attachment of a lactate-derived lactyl group. By high-performance liquid chromatography (HPLC)–tandem mass spectrometry (MS/MS) and Western blotting analyses, the authors showed that lysine residues in histones H3, H4, H2A, and H2B were lactylated in HeLa cells and mouse bone marrow–derived macrophages (BMDMs). In cell lines and BMDMs, lactylation correlated with the amount of intracellular lactate, and inhibitors of glycolysis reduced histone lactylation. In vitro, primary macrophages exposed to proinflammatory stimuli that trigger glycolysis contained more lactylated histone H3 than did macrophages exposed to anti-inflammatory stimuli that promote oxidative phosphorylation and fatty acid oxidation. After inflammatory stimulation of BMDMs, the appearance of lactylated histones was concurrent with increased expression of tissue repair genes, such as Arg1 and MMP9, and decreased expression of the inflammatory genes Tnf, Nos2, and Cxcl10; also, it was inversely correlated with histone acetylation. In vivo, macrophages from tumors had more lactylated histones and increased expression of Arg1 and Vegfa compared with macrophages from normal tissues. Whereas loss of lactate dehydrogenase reduced histone lactylation and Arg1 expression in macrophages, supplementation with extracellular lactate reversed these effects. Furthermore, enzymatic assays and experiments with knockout cell lines suggested that the histone acetyl transferase p300 may facilitate lactylation. However, it remains unclear what enzymes may act as lactylation writers, readers, and erasers in macrophages. Together, these data describe a previously uncharacterized, posttranslational histone modification that depends on glycolytic activity and correlates with anti-inflammatory gene expression in macrophages (see commentary by Izzo and Wellen). This distinct mechanism may help explain the immunosuppression that is observed in high-lactate environments—such as the brain or tumors—or some of the consequences of abnormal gut flora.

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