Genetic Variants Reprogram Colorectal Cancer Through RNA Methylation
Source PublicationScientific Reports
Primary AuthorsHan, Jang, Kim et al.
Genome-wide association studies (GWAS) have been instrumental in pinpointing numerous single-nucleotide polymorphisms (SNPs) linked to various diseases, including cancer. Despite these crucial identifications, the precise molecular mechanisms by which these genetic variations contribute to disease susceptibility have largely remained elusive. While some research has delved into the direct transcriptional impacts of disease-associated SNPs, their influence on post-transcriptional regulation—the fine-tuning of gene expression after RNA is made—has been less thoroughly explored.
To bridge this knowledge gap, our research focused on investigating whether cancer-associated SNPs could influence gene expression by altering N6-methyladenosine (m6A) RNA methylation, a critical form of post-transcriptional modification. We meticulously gathered GWAS-identified SNPs spanning nine different cancer types and integrated this data with matched tumor and normal m6A RNA immunoprecipitation sequencing (m6A-seq) and RNA sequencing (RNA-seq) datasets. This comprehensive approach allowed us to identify differentially methylated m6A sites and determine if cancer-associated SNPs were disproportionately located within these regions.
Our analyses yielded a significant discovery: cancer-associated SNPs were found to be remarkably enriched within hypermethylated m6A regions specifically in colon cancer. Further integrative analysis unveiled that these SNPs, localized in m6A-modified regions, are associated with altered gene expression and RNA splicing. This suggests that m6A methylation acts as a crucial mediator for the post-transcriptional impact of genetic variants. Experimental validation, through ALKBH5 knockdown, further confirmed these altered gene expression patterns, consistent with patient-derived data.
Ultimately, the study's collective findings reveal a significant link between genetic variants and cancer progression. As lead author Han notes in the paper, 'Collectively, our findings support a novel mechanistic connection between genetic variants and RNA methylation-driven transcriptomic regulation in colorectal cancer, underscoring the epitranscriptome as a potential axis of oncogenic control.' This research highlights the epitranscriptome—the layer of epigenetic information on RNA—as a potential axis of oncogenic control, influenced by genetic variants.