Proper control of R-loop homeostasis is required for maintenance of gene expression and neuronal function during...

Area of Science:

• Molecular Biology
• Neuroscience
• Genetics

Background:

• Aging is characterized by cellular dysfunction and loss, with links between gene expression defects and neuropathies.
• R-loops (RNA-DNA hybrids) are crucial for transcription but their dysregulation is associated with cellular dysfunction and disease.
• The role of R-loop homeostasis in aging neurons and its impact on gene expression remain unclear.

Purpose of the Study:

• To investigate the R-loop landscape in aging Drosophila melanogaster photoreceptor neurons.
• To determine the functional consequences of R-loop dysregulation on gene expression and visual function during aging.

Main Methods:

• Genome-wide mapping of R-loops in aging fly photoreceptor neurons.
• Analysis of gene expression changes correlated with R-loop accumulation.
• Functional assessment of visual responses following manipulation of R-loop resolving enzymes (Top3β and RNase H1).

Main Results:

• Bulk R-loop levels increased with age in fly photoreceptor neurons.
• Aging correlated with R-loop accumulation over gene bodies, linked to decreased expression of long, highly expressed genes.
• Reduced Top3β impaired visual function, while over-expression of Top3β or RNase H1 enhanced visual responses in aged flies.

Conclusions:

• Dysregulation of R-loop homeostasis is a key factor in age-related decline of neuronal function.
• R-loop accumulation during aging directly impacts gene expression homeostasis and visual performance.
• Targeting R-loop resolution pathways offers a potential therapeutic strategy for age-related visual dysfunction.