Lactate and histone H3K18 lactylation are associated with metabolic control of gene expression in the retina [explant_RNA-seq 2]

High aerobic glycolysis in retinal photoreceptors, as in cancer cells, is implicated in mitigating energy and metabolic demands. Lactate, a key product of glycolysis, is implicated in epigenetic regulation through histone lactylation in cancer. Here, we demonstrate that increased ATP production during retinal development is achieved primarily through augmented glycolysis. Histone lactylation, especially H3K18La, parallels enhanced glycolysis and its product, lactate, in developing retina and in retinal explants. Multi-omics analyses, combined with confocal imaging, reveal the localization of H3K18La near H3K27Ac in euchromatin at promoters of active retinal, especially photoreceptor, genes. H3K18La and gene expression also correspond to glucose metabolism in retinal explants. Evaluation of accessible chromatin at H3K18La promoters uncovers an enrichment of GC-rich motifs for transcription factors of SP, KMT and KLF families, among others, indicating specificity of H3K18La-mediated gene regulation. Our results highlight glycolysis/lactate/H3K18La as a regulatory axis in fine-tuning gene expression in developing and mature retina. Overall design: Biologically replicated RNA-seq was performed on retinal explant cultures. The dissected retinas were incubated in Neurobasal-A media supplemented with 5 mM glucose with and without 20 mM 2-DG. Gene-level differential expression analysis was performed using RNA-seq data.