Mapping the daily rhythmic transcriptome in the diabetic retina

Dec 1, 2023Vision research

Daily patterns of gene activity in the diabetic retina

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Abstract

The retinal transcriptome shows a clear 12-hour transcriptional axis that is phase advanced in some genes in diabetic mice compared to non-diabetic littermates.

Diabetes affects the daily rhythm of gene expression in the retina, which changes significantly from day to night.
Daytime genes are linked to DNA repair, RNA splicing, and ribosomal protein synthesis, while nighttime genes are associated with metabolic processes and growth factor signaling.
Some genes in the diabetic retina are phase advanced, indicating a shift in their expression timing compared to healthy retinas.
Oxygen-sensing mechanisms and HIF1alpha are involved in the phase-shifted genes, while the circadian clock remains synchronized with the light/dark cycle.
Internal desynchrony with the circadian clock may occur early in diabetes, affecting retinal metabolic pathways related to neuronal dysfunction and hypoxia.

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Retinal function changes dramatically from day to night, yet clinical diagnosis, treatments, and experimental sampling occur during the day. To begin to address this gap in our understanding of disease pathobiology, this study investigates whether diabetes affects the retina's daily rhythm of gene expression. Diabetic, Ins2mice, and non-diabetic littermates were kept under a 12 h:12 h light/dark cycle until 4 months of age. mRNA sequencing was conducted in retinas collected every 4 h throughout the 24 hr light/dark cycle. Computational approaches were used to detect rhythmicity, predict acrophase, identify differential rhythmic patterns, analyze phase set enrichment, and predict upstream regulators. The retinal transcriptome exhibited a tightly regulated rhythmic expression with a clear 12-hr transcriptional axis. Day-peaking genes were enriched for DNA repair, RNA splicing, and ribosomal protein synthesis, night-peaking genes for metabolic processes and growth factor signaling. Although the 12-hr transcriptional axis is retained in the diabetic retina, it is phase advanced for some genes. Upstream regulator analysis for the phase-shifted genes identified oxygen-sensing mechanisms and HIF1alpha, but not the circadian clock, which remained in phase with the light/dark cycle. We propose a model in which, early in diabetes, the retina is subjected to an internal desynchrony with the circadian clock and its outputs are still light-entrained whereas metabolic pathways related to neuronal dysfunction and hypoxia are phase advanced. Further studies are now required to evaluate the chronic implications of such desynchronization on the development of diabetic retinopathy. Akita/J

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Mapping the daily rhythmic transcriptome in the diabetic retina

Abstract

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