A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing

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

doi:10.1038/ng1972

A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

812 Scopus citations

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.

Original language	English (US)
Pages (from-to)	237-242
Number of pages	6
Journal	Nature genetics
Volume	39
Issue number	2
DOIs	https://doi.org/10.1038/ng1972
State	Published - Feb 2007

ASJC Scopus subject areas

Genetics

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Ohm, J. E., McGarvey, K. M., Yu, X., Cheng, L., Schuebel, K. E., Cope, L., Mohammad, H. P., Chen, W., Daniel, V. C., Yu, W., Berman, D. M., Jenuwein, T., Pruitt, K., Sharkis, S. J., Watkins, D. N., Herman, J. G., & Baylin, S. B. (2007). A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nature genetics, 39(2), 237-242. https://doi.org/10.1038/ng1972

Ohm, JE, McGarvey, KM, Yu, X, Cheng, L, Schuebel, KE , Cope, L, Mohammad, HP, Chen, W, Daniel, VC, Yu, W, Berman, DM, Jenuwein, T, Pruitt, K, Sharkis, SJ, Watkins, DN, Herman, JG & Baylin, SB 2007, 'A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing', Nature genetics, vol. 39, no. 2, pp. 237-242. https://doi.org/10.1038/ng1972

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title = "A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing",

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.",

author = "Ohm, {Joyce E.} and McGarvey, {Kelly M.} and Xiaobing Yu and Linzhao Cheng and Schuebel, {Kornel E.} and Leslie Cope and Mohammad, {Helai P.} and Wei Chen and Daniel, {Vincent C.} and Wayne Yu and Berman, {David M.} and Thomas Jenuwein and Kevin Pruitt and Sharkis, {Saul J.} and Watkins, {D. Neil} and Herman, {James G.} and Baylin, {Stephen B.}",

note = "Funding Information: Special thanks to L. Meszler (Cell Imaging Core Facility, The Sidney Kimmel Comprehensive Cancer Center), P. Argani (Pathology Department, Johns Hopkins University) and G. Dimri (Northwestern University) for providing the Bmi1cDNA. The pBABE-puro retroviral construct was provided by G. Dimri (Northwestern University). This work was supported by US National Institutes of Health grants CA116160 to S.B.B. and HL073781 to L.C. and National Cancer Institute grant CA043318 to S.B.B.",

year = "2007",

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doi = "10.1038/ng1972",

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AU - Ohm, Joyce E.

AU - McGarvey, Kelly M.

AU - Yu, Xiaobing

AU - Cheng, Linzhao

AU - Schuebel, Kornel E.

AU - Cope, Leslie

AU - Mohammad, Helai P.

AU - Chen, Wei

AU - Daniel, Vincent C.

AU - Yu, Wayne

AU - Berman, David M.

AU - Jenuwein, Thomas

AU - Pruitt, Kevin

AU - Sharkis, Saul J.

AU - Watkins, D. Neil

AU - Herman, James G.

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N1 - Funding Information: Special thanks to L. Meszler (Cell Imaging Core Facility, The Sidney Kimmel Comprehensive Cancer Center), P. Argani (Pathology Department, Johns Hopkins University) and G. Dimri (Northwestern University) for providing the Bmi1cDNA. The pBABE-puro retroviral construct was provided by G. Dimri (Northwestern University). This work was supported by US National Institutes of Health grants CA116160 to S.B.B. and HL073781 to L.C. and National Cancer Institute grant CA043318 to S.B.B.

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N2 - 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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A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing

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