1. Composition and histone substrates of polycomb repressive group complexes change during cellular differentiation.
- Author
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Kuzmichev A, Margueron R, Vaquero A, Preissner TS, Scher M, Kirmizis A, Ouyang X, Brockdorff N, Abate-Shen C, Farnham P, and Reinberg D
- Subjects
- Animals, DNA-Binding Proteins, Enhancer of Zeste Homolog 2 Protein, Gene Expression Profiling, HeLa Cells, Histone-Lysine N-Methyltransferase, Humans, Macromolecular Substances, Male, Mice, Multigene Family, Oligonucleotide Array Sequence Analysis, Polycomb Repressive Complex 2, Polycomb-Group Proteins, Prostatic Neoplasms genetics, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Protein Isoforms genetics, Protein Isoforms metabolism, Proteins genetics, Proteins metabolism, RNA Interference, Sirtuin 1, Sirtuins genetics, Sirtuins metabolism, Substrate Specificity, Transcription Factors, Cell Differentiation physiology, Gene Expression Regulation, Histones metabolism, Repressor Proteins genetics, Repressor Proteins metabolism
- 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.
- Published
- 2005
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