Genome-wide identification and characterization of circular RNA m⁶A modification in pancreatic cancer

N⁶-methyladenosine (m⁶A) is the most abundant modification of RNA in eukaryotic cells and play critical roles in cancer. While most related studies focus on m⁶A modifications in linear RNA, transcriptome-wide profiling and exploration of m⁶A modification in circular RNAs in cancer is still lacking.

For the detection of m⁶A modification in circRNAs, we developed a new bioinformatics tools called Circm6A and applied it to the m⁶A-seq data of 77 tissue samples from 58 individuals with pancreatic ductal adenocarcinoma (PDAC).

Circm6A performs better than the existing circRNA identification tools, which achieved highest F1 score among these tools in the detection of circRNAs with m⁶A modifications. By using Circm6A, we identified a total of 8807 m⁶A-circRNAs from our m⁶A-seq data. The m⁶A-circRNAs tend to be hypermethylated in PDAC tumor tissues compared with normal tissues. The hypermethylated m⁶A-circRNAs were associated with a significant gain of circRNA-mRNA coexpression network, leading to the dysregulation of many important cancer-related pathways. Moreover, we found the cues that hypermethylated m⁶A-circRNAs may promote the circularization and translation of circRNAs.

These comprehensive findings further bridged the knowledge gaps between m⁶A modification and circRNAs fields by depicting the m⁶A-circRNAs genomic landscape of PDAC patients and revealed the emerging roles played by m⁶A-circRNAs in pancreatic cancer. Circm6A is available at https://github.com/canceromics/circm6a .