title: Embryonic Stem Cell (ES)-Specific Enhancers Specify the Expression Potential of ES Genes in Cancer.
abstract: Cancers often display gene expression profiles resembling those of undifferentiated cells. The mechanisms controlling these expression programs have yet to be identified. Exploring transcriptional enhancers throughout hematopoietic cell development and derived cancers, we uncovered a novel class of regulatory epigenetic mutations. These epimutations are particularly enriched in a group of enhancers, designated ES-specific enhancers (ESSEs) of the hematopoietic cell lineage. We found that hematopoietic ESSEs are prone to DNA methylation changes, indicative of their chromatin activity states. Strikingly, ESSE methylation is associated with gene transcriptional activity in cancer. Methylated ESSEs are hypermethylated in cancer relative to normal somatic cells and co-localized with silenced genes, whereas unmethylated ESSEs tend to be hypomethylated in cancer and associated with reactivated genes. Constitutive or hematopoietic stem cell-specific enhancers do not show these trends, suggesting selective reactivation of ESSEs in cancer. Further analyses of a hypomethylated ESSE downstream to the VEGFA gene revealed a novel regulatory circuit affecting VEGFA transcript levels across cancers and patients. We suggest that the discovered enhancer sites provide a framework for reactivation of ES genes in cancer.
authors.affiliation: Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada (IMRIC), The Hebrew University-Hadassah Medical School, Jerusalem, Israel.|Institute for Computational Health Sciences, University of California, San Francisco, California, United States of America.
authors.forename: Dvir
authors.initials: D
authors.lastname: Aran
authors.affiliation: Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada (IMRIC), The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Monther
authors.initials: M
authors.lastname: Abu-Remaileh
authors.affiliation: Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada (IMRIC), The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Revital
authors.initials: R
authors.lastname: Levy
authors.affiliation: Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada (IMRIC), The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Nurit
authors.initials: N
authors.lastname: Meron
authors.affiliation: Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada (IMRIC), The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Gidon
authors.initials: G
authors.lastname: Toperoff
authors.affiliation: Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada (IMRIC), The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Yifat
authors.initials: Y
authors.lastname: Edrei
authors.affiliation: Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada (IMRIC), The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Yehudit
authors.initials: Y
authors.lastname: Bergman
authors.affiliation: Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada (IMRIC), The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Asaf
authors.initials: A
authors.lastname: Hellman
mesh_terms: D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D004742:Enhancer Elements, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006410:Hematopoiesis / Q000235:genetics; D000066449:Human Embryonic Stem Cells / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D063146:Polycomb-Group Proteins / Q000378:metabolism; D015203:Reproducibility of Results; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D063146:Polycomb-Group Proteins; D042461:Vascular Endothelial Growth Factor A