Differentially Methylated Super-Enhancers Regulate Target Gene Expression in Human Cancer

Area of Science:

• Oncology
• Epigenetics
• Genomics

Background:

• Super-enhancers (SEs) are crucial for aberrant gene expression in cancers.
• Limited chromatin data hinders the identification of cancer-specific SEs and their roles in carcinogenesis.
• Human papillomavirus-related oropharyngeal squamous cell carcinoma (HPV+ OPSCC) exhibits significant gene expression changes not explained by genetic alterations alone.

Purpose of the Study:

• To develop a computational pipeline for discovering tissue-specific SEs and their target genes using data from etiologically similar tumors.
• To apply this pipeline to HPV+ OPSCC, leveraging existing chromatin data from related tissues.
• To identify functional SEs and their target genes critical for HPV+ OPSCC development.

Main Methods:

• Developed a pipeline integrating gene expression and DNA methylation data.
• Utilized public domain SE data from normal/tumor lung and cervical cancer cell lines.
• Filtered candidate SEs using HPV+ OPSCC methylation and expression data to identify functional SEs and target genes.

Main Results:

• Identified 159 differentially methylated SEs in HPV+ OPSCC, with 87 actively regulating 150 nearby genes (211 SE-gene pairs).
• Validated 132 SE-gene pairs in a TCGA cohort.
• Pathway analysis linked SE-regulated genes to carcinogenesis pathways in nasopharyngeal, breast, melanoma, and bladder cancers.

Conclusions:

• Epigenetic alterations in SEs, common across related tissues, may control gene expression in HPV+ OPSCC.
• The developed pipeline is adaptable for SE analysis in various diseased and non-diseased tissues.
• This approach facilitates the discovery of cancer-driving epigenetic mechanisms where direct tumor data is scarce.