Aberrant DNA methylation defines isoform usage in cancer, with functional implications

Area of Science:

• Cancer Biology
• Epigenetics
• Transcriptomics

Background:

• Alternative transcript isoforms are prevalent in tumors and can drive cancer progression.
• Mechanisms like mutations and altered splicing factors influence isoform expression.
• DNA methylation regulates isoform activity in normal cells, suggesting a similar role in cancer.

Purpose of the Study:

• To investigate the impact of dysregulated DNA methylation on alternative transcript isoform activity in cancer.
• To determine if DNA methylation patterns correlate with specific isoform usage across various cancer types.
• To explore the functional consequences of methylation-driven isoform changes in tumor classification and protein function.

Main Methods:

• Analysis of DNA methylation and RNA-sequencing isoform data from 18 human cancer types.
• Identification of correlations between methylation sites and isoform expression.
• Examination of CpG site location's influence on isoform selection.
• Classification of tumors based on methylation-isoform patterns.

Main Results:

• Frequent correlations between DNA methylation and isoform expression were observed in 11 out of 18 cancer types.
• The location of methylated CpG sites significantly influenced the choice of transcript isoform.
• Methylation-isoform patterns effectively classified tumors into known subtypes.
• These patterns predicted distinct protein functions and pathway enrichments, including oncogenes and tumor suppressors.

Conclusions:

• Dysregulated DNA methylation significantly impacts alternative transcript isoform activity in cancer.
• Epigenetic modifications play a crucial role in shaping the cancer transcriptome.
• Methylation-correlated isoforms are functionally relevant, linked to cancer-driving genes and pathways.