A Stem Cell-like Chromatin Pattern May Predispose Tumor Suppressor Genes to DNA Hypermethylation and Heritable Silencing

Overview

Journal Nat Genet

Specialty Genetics

Date 2007 Jan 11

PMID 17211412

Citations 538

Authors

Joyce E Ohm

Kelly M McGarvey

Xiaobing Yu

Linzhao Cheng

Kornel E Schuebel

Leslie Cope

Helai P Mohammad

Wei Chen

Vincent C Daniel

Wayne Yu

David M Berman

Thomas Jenuwein

Kevin Pruitt

Saul J Sharkis

D Neil Watkins

James G Herman

Stephen B Baylin

Affiliations

Soon will be listed here.

Abstract

Adult cancers may derive from stem or early progenitor cells. Epigenetic modulation of gene expression is essential for normal function of these early cells but is highly abnormal in cancers, which often show aberrant promoter CpG island hypermethylation and transcriptional silencing of tumor suppressor genes and pro-differentiation factors. We find that for such genes, both normal and malignant embryonic cells generally lack the hypermethylation of DNA found in adult cancers. In embryonic stem cells, these genes are held in a 'transcription-ready' state mediated by a 'bivalent' promoter chromatin pattern consisting of the repressive mark, histone H3 methylated at Lys27 (H3K27) by Polycomb group proteins, plus the active mark, methylated H3K4. However, embryonic carcinoma cells add two key repressive marks, dimethylated H3K9 and trimethylated H3K9, both associated with DNA hypermethylation in adult cancers. We hypothesize that cell chromatin patterns and transient silencing of these important regulatory genes in stem or progenitor cells may leave these genes vulnerable to aberrant DNA hypermethylation and heritable gene silencing during tumor initiation and progression.

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