Lactate and histone H3K18 lactylation are associated with metabolic control of gene expression in the retina

High aerobic glycolysis in retinal photoreceptors, as in cancer cells, is implicated in mitigating energy and metabolic demands. Lactate, a product of glycolysis, can exert epigenetic regulation through histone lactylation in cancer. Here, we show that enhanced ATP production during mouse retinal development is achieved primarily through increase in glycolysis. Histone lactylation, especially H3K18La, parallels increased glycolysis and lactate levels in the developing retina. Multi-omics analyses, combined with confocal imaging, reveal the localization of H3K18La near H3K27Ac in the euchromatin at promoters of active retinal genes. In mouse retinal explants, glucose metabolism is associated with lactate levels as well as H3K18La and consequently gene expression. However, inhibition of glycolysis with 2-deoxyglucose (2-DG) reduces global H3K18La and H3K27Ac marks with somewhat distinct transcriptional changes. Evaluation of accessible chromatin at H3K18La-marked promoters uncovers an enrichment of GC-rich motifs for transcription factors of SP, KMT and KLF families, among others, indicating the specificity of H3K18La-mediated gene regulation. Our results indicate glycolysis/lactate/H3K18La as a potential axis for transcriptional response to changing metabolic conditions in the retina, especially photoreceptors.