Extracellular lactate improves neurogenesis by modulating H3K9 lactylation and SnoN expression under hypoxic conditions.

BACKGROUND: Lactate has a beneficial effect on adult neurogenesis and has been identified as a mediator of lactylation of proteins. However, the regulatory role and function of histone lactylation in neurogenesis remain poorly understood. This study aimed to elucidate the relationship between lactate and the fate of neural stem cells (NSCs), and explore the role of histone lactylation in neurogenesis. METHODS: Under hypoxic conditions, NSCs were treated with lactate to investigate its effects on cell fate. Western blot and immunofluorescence staining were performed to detect histone lactylation modifications. RNA-sequencing (RNA-seq) was used to characterize the transcriptome after lactate treatment, in conjunction with Chromatin immunoprecipitation sequencing (ChIP-seq), to identify potential target genes for histone lactylation. RESULTS: Under hypoxic conditions, L-lactate promotes neurogenesis and induces H3K9 histone lactylation (H3K9la). The inhibition of L-lactate uptake or production hinders neuronal development and is accompanied by decreased H3K9la. And the inhibition of H3K9la inhibits the differentiation of NSCs into neurons. Furthermore, H3K9la was enriched in the SnoN (also known as Skil) promoter region, and siRNA targeting SnoN inhibits the generation of Doublecortin (DCX)(+) neurons. CONCLUSION: L-lactate promotes neurogenesis through H3K9la/SnoN axis under hypoxic environments and SnoN potentially serves as a novel target for enhancing neurological recovery in cerebral ischemia.