NEI study links glucose metabolism to gene control in retinal photoreceptors

Scientists at the National Eye Institute (NEI) have found that the way the retina metabolizes glucose directly influences which genes are activated in photoreceptor cells, a finding that may help explain how metabolic changes in aging and disease contribute to retinal conditions such as age-related macular degeneration (AMD). The research was funded by the NEI Intramural Research Program.^1,2

The study’s first author is Mohita Gaur, PhD, a postdoctoral fellow in the NEI Retinal Development, Genetics and Therapy Section.¹

The study, published in PLoS Genetics, examined how glucose metabolism affects gene expression in light-sensing photoreceptors, which rely on glucose for both energy and structural maintenance. Photoreceptors continuously replace discs at the tips of their outer segments to maintain cell health.^1,2

“We show that glucose metabolism controls expression of critical photoreceptor genes by epigenome changes,” said the study’s principal investigator, Anand Swaroop, PhD, chief of the Retinal Development, Genetics and Therapy Section at the NEI, part of the National Institutes of Health, in a news release.

Researchers focused on lactate, a byproduct of glucose metabolism, which chemically modifies DNA-packaging proteins called histones in photoreceptor cells. They identified a specific molecular marker, H3K18 lactylation (H3K18La), that rises and falls in response to how much glucose the retina is metabolizing.^1,2

“Dynamics of histone lactylation at specific cis-regulatory elements likely fine-tunes gene expression patterns during retinal development and under distinct metabolic environments,” the study authors stated. “The reversible nature of histone lactylation presents an opportunity for designing therapies as well as dietary paradigms as indicated by epidemiological studies.”

Using mouse retinas at multiple stages of development, the researchers measured glycolysis, the process that converts glucose to lactate, and mapped where H3K18La tags appeared across the genome.^1,2

They also grew isolated mouse retinas in laboratory dishes and exposed them either to extra glucose or to a drug that blocks glycolysis. They then measured changes in both the molecular tags and gene expression, according to the release.²

The researchers found that higher glucose levels led to more lactate production, increased H3K18La tagging, and greater expression of genes involved in light detection, photoreceptor development, and maintenance.^1,2

When glycolysis was blocked, the opposite occurred, with reduced H3K18La tagging and broad suppression of gene expression, according to the release.²

The team also found that H3K18La tags cluster at gene control regions alongside another activating marker, H3K27Ac. These tagged regions were recognized by a specific family of regulatory proteins, suggesting the mechanism is targeted rather than a general metabolic effect.^1,2

“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 Gaur in the release

References:

1. Gaur M, Brooks MJ, Liang X, et al. Lactate and histone H3K18 lactylation are associated with metabolic control of gene expression in the retina. PLOS Genetics. 2026. https://doi.org/10.1371/journal.pgen.1012100

2. NIH research points to new therapeutic opportunities for retinal diseases. News release. National Institute of Health, National Eye Institute. April 28, 2026. Accessed April 30, 2026. https://www.nei.nih.gov/research-and-training/research-news/nih-research-points-new-therapeutic-opportunities-retinal-diseases