title: Enhancer methylation dynamics contribute to cancer plasticity and patient mortality.
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 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.
authors.affiliation: Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel;
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Bell
authors.affiliation: Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel;
authors.forename: Tamar
authors.initials: T
authors.lastname: Golan
authors.affiliation: Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel;
authors.forename: Danna
authors.initials: D
authors.lastname: Sheinboim
authors.affiliation: Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel;
authors.forename: Hagar
authors.initials: H
authors.lastname: Malcov
authors.affiliation: Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv 69978, Israel;
authors.forename: David
authors.initials: D
authors.lastname: Amar
authors.affiliation: Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Avi
authors.initials: A
authors.lastname: Salamon
authors.affiliation: Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel;
authors.forename: Tamar
authors.initials: T
authors.lastname: Liron
authors.affiliation: Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel;
authors.forename: Sahar
authors.initials: S
authors.lastname: Gelfman
authors.affiliation: Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Yankel
authors.initials: Y
authors.lastname: Gabet
authors.affiliation: Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv 69978, Israel;
authors.forename: Ron
authors.initials: R
authors.lastname: Shamir
authors.affiliation: Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel;
authors.forename: Carmit
authors.initials: C
authors.lastname: Levy
mesh_terms: D045744:Cell Line, Tumor; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000401:mortality
chemical_list: D004273:DNA, Neoplasm