Genome-wide analysis reveals that exon methylation facilitates its selective usage in the human transcriptome

Area of Science:

• Epigenetics
• Genomics
• Molecular Biology

Background:

• DNA methylation is a key epigenetic regulator of gene expression, primarily studied in promoter regions.
• The role of intragenic DNA methylation in exon usage and alternative splicing remains largely unexplored.

Purpose of the Study:

• To comprehensively map the human DNA methylome across 10 tissues.
• To investigate the relationship between DNA methylation and gene/exon expression.
• To identify methylation-driven exon dysregulation in lung cancer and its prognostic potential.

Main Methods:

• Whole-genome bisulfite sequencing (WGBS) for DNA methylome profiling.
• Analysis of gene and exon expression data from human tissues and lung cancer samples.
• Statistical correlation analyses and pathway enrichment.

Main Results:

• Conserved and tissue-specific DNA methylation patterns were observed across the human genome.
• Promoter and first exon methylation negatively correlated with gene expression.
• Intragenic exon methylation showed a positive correlation with its own expression, with skip-in exons being more methylated.
• 260 differentially methylated and expressed exons were identified in lung cancer, linked to cancer hallmarks.
• A 10-exon signature demonstrated prognostic value for lung cancer.

Conclusions:

• Intragenic DNA methylation plays a significant role in regulating exon usage and alternative splicing.
• Aberrant intragenic methylation and exon expression are implicated in lung cancer development and prognosis.
• This study provides novel insights into the functional landscape of the DNA methylome beyond promoter regulation.