Enhancer methylation dynamics contribute to cancer plasticity and patient mortality
| Autor: | Carmit Levy, Yankel Gabet, Tamar Golan, Hagar Malcov, Danna Sheinboim, Tamar Liron, Ron Shamir, Rachel E. Bell, Avi Salamon, Sahar Gelfman, David Amar |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Biology Bioinformatics Metastasis 03 medical and health sciences Cell Line Tumor Genetics medicine Humans Epigenetics Melanoma Genetics (clinical) Research Bone metastasis Cancer DNA Neoplasm DNA Methylation medicine.disease Enhancer Elements Genetic 030104 developmental biology Differentially methylated regions Tumor progression DNA methylation Cancer cell Female |
| Zdroj: | Genome Research. 26:601-611 |
| ISSN: | 1549-5469 1088-9051 |
| DOI: | 10.1101/gr.197194.115 |
| Popis: | 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 seven body sites of metastatic melanoma. We found that enhancers are consistently the most differentially methylated regions (DMR) as cancer progresses 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 the 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 by the 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. |
| Databáze: | OpenAIRE |
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