G-quadruplexes originating from evolutionary conserved L1 elements interfere with neuronal gene expression in...

Area of Science:

• Neuroscience
• Genetics
• Epigenetics

Background:

• G-quadruplexes (G4) are stable DNA structures formed by guanine-rich sequences.
• Polycomb group protein BMI1 is crucial for maintaining heterochromatin and gene silencing.
• Altered chromatin states are implicated in neurodegenerative diseases like Alzheimer's disease (AD).

Purpose of the Study:

• To investigate the relationship between BMI1, G4 structures, and chromatin state in neurons.
• To explore the role of G4 structures in Alzheimer's disease pathogenesis.
• To identify the genomic locations and regulatory factors associated with G4 accumulation.

Main Methods:

• Chromatin immunoprecipitation sequencing (ChIP-seq) to map G4 and BMI1 enrichment.
• Analysis of G4 structures in neuronal cells with varying BMI1 expression and chromatin states.
• Correlation analysis between G4 localization, L1 elements, and RNA Polymerase II (RNAPII) occupancy.

Main Results:

• BMI1 is enriched at heterochromatin regions with G4 DNA.
• G4 structures accumulate in cells with reduced BMI1 or relaxed chromatin, notably in AD neurons.
• G4 peaks colocalize with transcriptionally active Long Interspersed Element-1 (L1) sequences and RNAPII.
• Intragenic G4 structures impact splicing and reduce neuronal gene expression in AD.
• Inhibition of transcription reverses G4 accumulation without altering chromatin compaction.

Conclusions:

• BMI1 and chromatin compaction regulate G4 formation in neurons.
• Active L1 elements are a major source of G4 structures in human neurons.
• G4 accumulation in AD neurons is linked to L1 activity, splicing dysregulation, and reduced gene expression.