Enhancer methylation dynamics contribute to cancer plasticity and patient mortality
- Rachel E Bell,
- Tamar Golan,
- Hagar Malcov,
- David Amar,
- Avi Salamon,
- Tamar Liron,
- Danna Sheinboim,
- Sahar Gelfman,
- Yankel Gabet,
- Ron Shamir and
- Carmit Levy1
- ↵* Corresponding author; email: carmitlevy{at}post.tau.ac.il
Abstract
During development enhancers play pivotal roles in regulating gene expression programs; however, their involvement in cancer progression has not been fully characterized. We performed an integrative analysis of DNA methylation, RNA-seq and small RNA-seq profiles from thousands of patients, including 25 diverse primary malignances and 7 body sites of metastatic melanoma. We found that enhancers are consistently the most differentially methylated regions (DMR) as cancer progress from normal to primary tumors and then to metastases, compared to other genomic features. Remarkably, identification of enhancer DMRs (eDMRs) enabled classification of primary tumors according to physiological organ systems and in metastasis eDMRs are the most correlated with patient outcome. To further understand eDMR role in cancer progression we developed a model to predict genes and microRNAs that are regulated by enhancer and not promotor methylation, which shows high accuracy with chromatin architecture methods and was experimentally validated. Interestingly, among all metastatic melanoma eDMRs the most correlated with patient survival were eDMRs that 'switched' their methylation patterns back and forth between normal, primary and metastases and target cancer drivers, e.g.: KIT. We further demonstrated that eDMR target genes were modulated in melanoma bone metastasis microenvironment, suggesting that eDMRs respond to microenvironmental cues in metastatic niches. Our findings that aberrant methylation in cancer cells mostly affects enhancers, which contribute to tumor progression and cancer cell plasticity, will facilitate development of epigenetic anticancer approaches.
- Received July 21, 2015.
- Accepted February 19, 2016.
- Published by Cold Spring Harbor Laboratory Press
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