NIH research points to new therapeutic opportunities for retinal diseases

Confocal immunofluorescent images show colocalization of H3K27Ac and H3K18La in the nuclear periphery of photoceptor cells. Credit: Anand Swaroop, Ph.D.

National Eye Institute (NEI) scientists have found that the way the retina metabolizes glucose directly controls which genes get switched on and off in light-sensing photoreceptors. The findings suggest that metabolic disruptions seen in aging and disease may directly destabilize the gene expression needed to keep photoreceptors healthy, opening new avenues for treating retinal diseases such as age-related macular degeneration (AMD), a leading cause of vision loss. The work is published in PLoS Genetics.

"We show that glucose metabolism controls expression of critical photoreceptor genes by epigenome changes," said the study's principal investigator, Anand Swaroop, Ph.D., chief of the Retinal Development, Genetics and Therapy Section at the NEI, part of the National Institutes of Health.

Retinal photoreceptors depend on the availability of glucose for energy as well as for structural maintenance. On a daily basis, discs on the outer segment tips of photoreceptors get replaced, which helps the cell remain healthy.

For the study, the researchers leveraged the fact that lactate, a byproduct of glucose metabolism, chemically tags the DNA-packaging proteins (called histones) in photoreceptor cells. A specific molecular tag, called H3K18 lactylation (H3K18La), rises and falls in direct response to how much glucose the retina is metabolizing, acting as a live and dynamic readout of the metabolic state and expression of vision-related genes.

Studying mouse retinas at multiple stages of development, the researchers measured glycolysis, the process that converts glucose to lactate, while also mapping the precise locations of H3K18La tags across the entire genome.

They confirmed the presence of H3K18La tags to actual changes in gene expression by growing isolated mouse retinas in dishes, exposing them to either extra glucose or a drug that blocks glycolysis, and measured how both the molecular tags and gene expression responded.

The results were clear and consistent: more glucose meant more lactate, more H3K18La tagging, and higher expression of genes critical for vision, including those involved in light detection, photoreceptor development and maintenance.

Blocking glycolysis had the opposite effect, stripping away the tags and broadly suppressing gene expression. The team also found that H3K18La tags cluster at the control switches of genes alongside another known activating mark, H3K27Ac, and that the tagged regions are recognized by a specific family of regulatory regions of proteins, suggesting this is a precise, targeted system rather than a general metabolic side effect.

"Future studies will examine how H3K18La patterns change during aging and in disease models of AMD and diabetic retinopathy. We also plan to test whether dietary interventions that affect glucose metabolism can influence these epigenetic marks in a meaningful way," said the study's first author, Mohita Gaur, Ph.D., a postdoctoral fellow in the NEI Retinal Development, Genetics and Therapy Section.

The research was funded by the NEI Intramural Research Program.

Reference:

Gaur M, Brooks MJ, Liang X, Jiang K, Kumari A, English MA, et al. (2026) Lactate and histone H3K18 lactylation are associated with metabolic control of gene expression in the retina. PLoS Genet 22(4): e1012100. https://doi.org/10.1371/journal.pgen.1012100

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