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.
Highlights
Disruption of normal cellular identity is a hallmark of cancer cells [1]
We demonstrate that a particular subtype of transcriptional enhancers, which we termed embryonic stem cells (ES)-specific enhancers (ESSEs), are especially prone to DNA methylation perturbations in cancer
We explored the fate of ES enhancers during normal development of the hematopoietic cell lineage
Summary
Various cancer types display gene expression profiles that show similarities to the expression program of embryonic stem cells (ES), but are absent from the differentiated tissue from which the cancer evolves These ES and cancer-specific expression signatures comprise genes of the ES core module, including NANOG, OCT4, SOX2 and KLF4, the polycomb repressive complex 2 (PRC2) module including EZH2, EED, and SUZ12, the MYC module and other genes [2,3,4,5,6] (reviewed in [7]). Many of these genes participate in inter- and intra-cellular signaling pathways. The regulatory mechanisms underlying the establishment of ES-related expression profiles in cancer are not well understood
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