Mapping the daily rhythmic transcriptome in the diabetic retina.

Area of Science:

• Ophthalmology
• Chronobiology
• Molecular Biology

Background:

• Retinal function exhibits significant daily variations, yet research and clinical practices predominantly occur during daytime.
• Understanding the impact of diabetes on the retina's daily gene expression patterns is crucial for disease pathobiology insights.

Purpose of the Study:

• To investigate whether diabetes alters the daily rhythm of gene expression in the retina.
• To identify specific molecular pathways affected by diabetes-induced retinal desynchrony.

Main Methods:

• Utilized Ins2Akita/J diabetic and non-diabetic mice under a 12h:12h light/dark cycle.
• Performed mRNA sequencing on retinas collected every 4 hours over a 24-hour period.
• Employed computational analysis to detect rhythmicity, phase, differential patterns, and upstream regulators.

Main Results:

• The healthy retinal transcriptome shows a robust 12-hour rhythmic expression pattern, with distinct genes peaking during day (DNA repair, RNA splicing) and night (metabolism, growth factors).
• Diabetic retinas maintain the 12-hour rhythm but exhibit phase advancement in specific genes.
• Upstream regulator analysis identified oxygen-sensing mechanisms and HIF1alpha as phase-shifted, while the circadian clock remained synchronized with the light/dark cycle.

Conclusions:

• Early diabetes induces an internal desynchrony in the retina, where metabolic pathways related to neuronal dysfunction and hypoxia become phase-advanced relative to the light-entrained circadian clock.
• This desynchrony may play a role in the development of diabetic retinopathy.
• Further research is needed to assess the long-term consequences of this internal desynchrony.