Genetic variants reshape the m⁶A epitranscriptome and drive transcriptomic reprogramming in colorectal cancer

Area of Science:

• Genomics
• Epigenetics
• Cancer Biology

Background:

• Genome-wide association studies (GWAS) identify disease-associated single-nucleotide polymorphisms (SNPs), but their functional mechanisms are often unknown.
• While transcriptional effects of SNPs are studied, their post-transcriptional regulatory roles, particularly in RNA methylation, are less understood.

Purpose of the Study:

• To investigate if cancer-associated SNPs influence gene expression by altering N6-methyladenosine (m⁶A) RNA methylation.
• To explore the role of m⁶A RNA methylation in mediating the post-transcriptional effects of genetic variants in cancer.

Main Methods:

• Collected GWAS-identified SNPs across nine cancer types.
• Integrated SNP data with matched tumor and normal m⁶A RNA immunoprecipitation sequencing (m⁶A-seq) and RNA sequencing (RNA-seq) datasets.
• Identified differentially methylated m⁶A sites and assessed SNP enrichment; performed integrative analysis and experimental validation.

Main Results:

• Cancer-associated SNPs were significantly enriched in hypermethylated m⁶A regions in colon cancer.
• SNPs in m⁶A-modified regions correlated with altered gene expression and RNA splicing.
• Experimental validation confirmed altered gene expression linked to m⁶A modification, consistent with patient data.

Conclusions:

• A novel mechanistic link exists between genetic variants and RNA methylation-driven transcriptomic regulation in colorectal cancer.
• m⁶A RNA methylation mediates the post-transcriptional impact of genetic variants.
• The epitranscriptome represents a potential axis of oncogenic control.