RESUMO
Toll-like receptor (TLR) activation induces inflammatory responses in macrophages by activating temporally defined transcriptional cascades. Whether concurrent changes in the cellular metabolism that occur upon TLR activation influence the quality of the transcriptional responses remains unknown. Here, we investigated how macrophages adopt their metabolism early after activation to regulate TLR-inducible gene induction. Shortly after TLR4 activation, macrophages increased glycolysis and tricarboxylic acid (TCA) cycle volume. Metabolic tracing studies revealed that TLR signaling redirected metabolic fluxes to generate acetyl-Coenzyme A (CoA) from glucose resulting in augmented histone acetylation. Signaling through the adaptor proteins MyD88 and TRIF resulted in activation of ATP-citrate lyase, which in turn facilitated the induction of distinct LPS-inducible gene sets. We postulate that metabolic licensing of histone acetylation provides another layer of control that serves to fine-tune transcriptional responses downstream of TLR activation. Our work highlights the potential of targeting the metabolic-epigenetic axis in inflammatory settings.
Assuntos
ATP Citrato (pro-S)-Liase/metabolismo , Acetilcoenzima A/metabolismo , Histonas/metabolismo , Macrófagos/metabolismo , Receptor 4 Toll-Like/metabolismo , Acetilação , Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , Ciclo do Ácido Cítrico/fisiologia , Glicólise/fisiologia , Humanos , Lipopolissacarídeos/metabolismo , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Transdução de Sinais , Transcrição Gênica/genéticaRESUMO
The effect of one carbon metabolism on DNA methylation has been well described, bridging nutrition, metabolism, and epigenetics. This modification is mediated by the metabolite S-adenosyl methionine (SAM), which is also the methyl-donating substrate of histone methyltransferases. Therefore, SAM levels that are influenced by several nutrients, enzymes, and metabolic cofactors also have a potential impact on histone methylation. Although this modification plays a major role in chromatin accessibility and subsequently in gene expression in healthy or diseased states, its role in translating nutritional changes in chromatin structure has not been extensively studied. Here, we aim to review the literature of known mechanistic links between histone methylation and the central one carbon metabolism.