A Stem Cell-Like Chromatin Pattern May Predispose Tumor Suppressor Genes to DNA Hypermethylation

ABSTRACT: Many cancers may originate in stem or early progenitor cells 1-4 which depend on epigenetic modulation of gene expression for normal function (ref). We have studied whether epigenetic states in cancers, and particularly abnormal gene silencing associated with promoter DNA hypermethylation in CpG rich regions (refs), may represent links between cancer and stem cell epigenetic patterns. We studied embryonal carcinomas (EC) which are malignancies of embryonic stem (ES) cells, but retain high potential for multi-lineage differentiation 5-8. Surprisingly, genes DNA hypermethylated and silenced in adult cancers are unmethylated in ES and EC cells. Remarkably, the promoter chromatin of the genes in EC cells is virtually identical to the same genes in adult cancers when the latter are induced to de-methylate. This chromatin, as recently reported for CpG island promoters of low expression, developmentally related, genes in ES cells (refs), is “bivalent” and contains both active and repressive histone modifications. The latter includes trimethyl lysine 27 of histone H3 (H3K27me3), which may recruit DNA methylation (refs), and the promoter regions are enriched for polycomb group (PcG) proteins which place this H3K27me3 mark. Thus, many genes which undergo abnormal DNA methylation and permanent silencing in adult cancers may be programmed to do so by a pre-existent stem cell-like chromatin pattern inherent to the cells in which they arise. Keywords: Stem cell epigenetics expression microarray

ORGANISM(S): Homo sapiens

PROVIDER: GSE4809 | GEO | 2007/10/26

SECONDARY ACCESSION(S): PRJNA95717

REPOSITORIES: GEO