Abstract
Changes in the substrate specificities of factors that irreversibly modify the histone components of chromatin are expected to have a profound effect on gene expression through epigenetics. Ezh2 is a histone-lysine methyltransferase with activity dependent on its association with other components of the Polycomb Repressive Complexes 2 and 3 (PRC2/3). Ezh2 levels are increasingly elevated during prostate cancer progression. Other PRC2/3 components also are elevated in cancer cells. Overexpression of Ezh2 in tissue culture promotes formation of a previously undescribed PRC complex, PRC4, that contains the NAD+-dependent histone deacetylase SirT1 and isoform 2 of the PRC component Eed. Eed2 is expressed in cancer and undifferentiated embryonic stem (ES) cells but is undetectable in normal and differentiated ES cells. The distinct PRCs exhibit differential histone substrate specificities. These findings suggest that formation of a transformation-specific PRC complex may have a major role in resetting patterns of gene expression by regulating chromatin structure.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cell Differentiation / physiology*
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DNA-Binding Proteins
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Enhancer of Zeste Homolog 2 Protein
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Gene Expression Profiling
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Gene Expression Regulation*
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HeLa Cells
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Histone-Lysine N-Methyltransferase
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Histones / metabolism*
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Humans
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Macromolecular Substances
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Male
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Mice
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Multigene Family
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Oligonucleotide Array Sequence Analysis
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Polycomb Repressive Complex 2
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Polycomb-Group Proteins
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Proteins / genetics
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Proteins / metabolism
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RNA Interference
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Repressor Proteins / genetics*
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Repressor Proteins / metabolism*
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Sirtuin 1
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Sirtuins / genetics
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Sirtuins / metabolism
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Substrate Specificity
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Transcription Factors
Substances
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DNA-Binding Proteins
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Eed protein, mouse
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Histones
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Macromolecular Substances
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Polycomb-Group Proteins
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Protein Isoforms
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Proteins
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Repressor Proteins
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Transcription Factors
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EZH2 protein, human
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Enhancer of Zeste Homolog 2 Protein
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Ezh2 protein, mouse
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Histone-Lysine N-Methyltransferase
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Polycomb Repressive Complex 2
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Sirt1 protein, mouse
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Sirtuin 1
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Sirtuins