Temporally specific gene expression and chromatin remodeling programs regulate a conserved Pdyn enhancer.

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Neuronal adaptations involve gene expression waves, with immediate early genes (IEGs) regulating late response genes (LRGs).
• The molecular mechanisms linking IEGs to LRGs and enduring plasticity are not well understood.

Approach:

• Transcriptomic and chromatin accessibility profiling in rat striatal neurons after depolarization.
• CRISPR-based functional assays to validate enhancer activity.
• Comparative analysis of regulatory elements in rat and human genomes.

Key Points:

• Neuronal depolarization induces IEG expression within 1 hour and LRG expression, synaptic proteins, and chromatin remodeling at 4 hours.
• Activity-dependent transcription factors, like AP-1, bind to newly accessible non-coding regulatory elements.
• IEG proteins are required for activity-dependent chromatin remodeling.

Conclusions:

• IEGs play a crucial role in activity-dependent chromatin remodeling at enhancers.
• A conserved enhancer upstream of Pdyn (prodynorphin) is identified, regulating its transcription.
• This Pdyn enhancer represents a potential therapeutic target for neuropsychiatric disorders involving Pdyn dysregulation.