A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing.
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.
Ohm
Joyce E
JE
Cancer Biology Division, The Sidney Kimmel Comprehensive Cancer Center.
McGarvey
Kelly M
KM
Yu
Xiaobing
X
Cheng
Linzhao
L
Schuebel
Kornel E
KE
Cope
Leslie
L
Mohammad
Helai P
HP
Chen
Wei
W
Daniel
Vincent C
VC
Yu
Wayne
W
Berman
David M
DM
Jenuwein
Thomas
T
Pruitt
Kevin
K
Sharkis
Saul J
SJ
Watkins
D Neil
DN
Herman
James G
JG
Baylin
Stephen B
SB
D000328:Adult; D049109:Cell Proliferation; D002843:Chromatin / Q000378:metabolism*; D019175:DNA Methylation; D053595:Embryonic Stem Cells / Q000378:metabolism; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006657:Histones / Q000378:metabolism; D006801:Humans; D063146:Polycomb-Group Proteins; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D002843:Chromatin; D006657:Histones; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins