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John R Edwards

Publications and source records attributed to John R Edwards.

2 recordsLinked to original sources

MIGS: Methylation Interpolated Gene Signatures Determine Associations Between Differential Methylation and Gene Expression

A large number of genomic studies are underway to determine which genes are abnormally regulated by methylation in disease. However, our understanding of how disease-specific methylation changes potentially affect expression is poorly understood. We need better tools to explain specific variation in methylation that potentially affects gene expression in clinical sequencing. We have developed a model, Methylation Interpolated Gene Signatures (MIGS), that captures the complexity of DNA methylation changes around a gene promoter. Using data from the Roadmap Epigenomics Project, we show that MIGS significantly outperforms current methods to use methylation data to predict differential expression. We find that methylation changes at the TSS and downstream ~2kb are most predictive of expression change. MIGS will be an invaluable tool to analyze genome-wide methylation data as MIGS produces a longer and more accurate list of genes with methylation-associated expression changes.

Bioinformatics

Epigenetic activation of the prostaglandin receptor EP4 promotes resistance to endocrine therapy for breast cancer

Approximately 75% of breast cancers express estrogen receptor (ER) and depend on estrogen signals for continued growth. Aromatase inhibitors (AIs) prevent estrogen production and inhibit estrogen receptor signaling, resulting in decreased cancer recurrence and mortality. Advanced tumors treated with AIs almost always develop resistance to these drugs via the up-regulation of alternative growth signals. The mechanisms that drive this resistance--especially epigenetic events that alter gene expression--are however not well understood. Genome-wide DNA methylation and expression analysis of cell line models of acquired aromatase inhibitor resistance indicated that prostaglandin E2 receptor 4 (PTGER4) is up-regulated after demethylation in resistant cells. Knockdown and inhibitor studies demonstrate that PTGER4 is essential for estrogen independent growth. Analysis of downstream signaling indicates that PTGER4 likely promotes AI resistance via ligand independent activation of the ER-cofactor CARM1. We believe that we have discovered a novel epigenetic mechanism for altering cell signaling and acquiring endocrine therapy resistance. Our findings indicate that PTGER4 is a potential drug target in AI resistant cancers. Additionally, the epigenetic component of PTGER4 regulation suggests that further study of PTGER4 may yield valuable insights into how DNA methylation-targeted diagnoses and treatments can improve AI resistant breast cancer treatment.

Cancer Biology