Comprehensive analysis of TCGA data reveals correlation between DNA methylation and alternative splicing

• Type of Material: Article
• Authors: Shuting Lin, Georgia Institute of Technology; Soojin Yi, University of California, Santa Barbara; Peng Qiu, Emory University
• Language: English
• Date: 2022-12-01
• Publisher: Springer Nature
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2022
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s12864-022-08992-w
• Title of Journal or Parent Work: BMC Genomics
• Volume: 23
• Issue: 1
• Start Page: 758
• End Page: 758
• Grant/Funding Information: This work was supported by funding from the National Science Foundation (CCF1552784 and CCF2007029). PQ is an ISAC Marylou Ingram Scholar, a Carol Ann and David D. Flanagan Faculty Fellow, and a Wallace H. Coulter Distinguished Faculty Fellow.
• Keywords: DNA methylation; Neoplasms; Exons; Survival analysis; Alternative splicing; Alternative Splicing; DNA Methylation; Exon; Correlation analysis; Humans
• Research Categories: Engineering, Biomedical

Abstract

The effect of DNA methylation on the regulation of gene expression has been extensively discussed in the literature. However, the potential association between DNA methylation and alternative splicing is not understood well. In this study, we integrated multiple omics data types from The Cancer Genome Atlas (TCGA) and systematically examined the relationship between DNA methylation and alternative splicing. Using the methylation data and exon expression data, we identified many CpG sites significantly associated with exon expression in various types of cancers. We further observed that the direction and strength of significant CpG-exon correlation tended to be consistent across different cancer contexts, indicating that some CpG-exon correlation patterns reflect fundamental biological mechanisms that transcend tissue- and cancer- types. We also discovered that CpG sites correlated with exon expressions were more likely to be associated with patient survival outcomes compared to CpG sites that did not correlate with exon expressions. Furthermore, we found that CpG sites were more strongly correlated with exon expression than expression of isoforms harboring the corresponding exons. This observation suggests that a major effect of CpG methylation on alternative splicing may be related to the inclusion or exclusion of exons, which subsequently impacts the relative usage of various isoforms. Overall, our study revealed correlation patterns between DNA methylation and alternative splicing, which provides new insights into the role of methylation in the transcriptional process.