Investigating the role of CpG islands and DNA methylation at 3'UTRs in cancer.

DNA methylation is one of the most important epigenetic processes that regulates gene expression. Although the human genome is predominantly methylated, CpG-rich regions known as CpG islands (CGIs) are typically unmethylated and are often sites of transcriptional control. Although the importance of CGIs and DNA methylation at the promoters is well understood, the significance of CGIs at the 3' ends remains largely unexplored. In this study, we characterised CGIs overlapping 3' untranslated regions (3'UTRs), compared them with CGIs located at the promoters, and examined their association with gene expression in cancer. We found that 3% of CGIs overlap 3'UTRs and have no annotated promoters in the vicinity. Unlike promoter CGIs, 3'UTR CGIs are shorter, less CpG-dense, but evolutionarily conserved. Although promoter CGIs typically stay unmethylated, those in 3'UTRs are often methylated and enriched for transcription factors like ZFP57, which target methylated motifs. These regions are linked to cancer signalling pathways, and their differential methylation in tumours correlates with gene expression changes, suggesting an underexplored regulatory role in cancer.