Embryonic Stem Cell (ES)-Specific Enhancers Specify the Expression Potential of ES Genes in Cancer

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...

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Bibliographic Details
Published in:PLoS genetics 2016-02, Vol.12 (2), p.e1005840-e1005840
Main Authors: Aran, Dvir, Abu-Remaileh, Monther, Levy, Revital, Meron, Nurit, Toperoff, Gidon, Edrei, Yifat, Bergman, Yehudit, Hellman, Asaf
Format: Article
Language:English
Subjects:
Biology and life sciences
Cancer
Cell Line, Tumor
Cell Lineage - genetics
Deoxyribonucleic acid
DNA
DNA methylation
DNA Methylation - genetics
Embryonic stem cells
Enhancer Elements, Genetic
Epigenetics
Gene expression
Gene Expression Regulation, Neoplastic
Genetic aspects
Genomes
Grants
Health aspects
Hematopoiesis - genetics
Human Embryonic Stem Cells - metabolism
Humans
Lymphocytes
Medical research
Medicine and Health Sciences
Neoplasms - genetics
Neoplasms - pathology
Polycomb-Group Proteins - metabolism
Reproducibility of Results
Stem cells
Vascular Endothelial Growth Factor A - genetics
Vascular Endothelial Growth Factor A - metabolism
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Summary: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.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1005840