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

PLoS Genetics
Dvir AranAsaf Hellman

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 ...Continue Reading

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Citations

Feb 28, 2018·Cellular and Molecular Life Sciences : CMLS·Leonidas Benetatos, George Vartholomatos
Apr 11, 2018·Frontiers in Cell and Developmental Biology·Qifan ZhuRamiro Alberio
Jul 29, 2021·NAR Cancer·Sara DahanMaayan Salton

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Datasets Mentioned

BETA
GSE16347
GSE39089
HUES9
WA09
GSM1004647
GM12093

Methods Mentioned

BETA
ChIP-seq
PCR
transfection
FACS

Software Mentioned

MxPro QPCR
Genomic Regions Enrichment of Annotations Tool ( GREAT )
4C
seqpipe
GREAT
Affymetrix Expression Console
MSigDB
MxPro qPCR system

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