Abstract
Methylation of histone H3 lysine 27 (H3K27) is a posttranslational modification that is highly correlated with genomic silencing. Here we show that human UTX, a member of the Jumonji C family of proteins, is a di- and trimethyl H3K27 demethylase. UTX occupies the promoters of HOX gene clusters and regulates their transcriptional output by modulating the recruitment of polycomb repressive complex 1 and the monoubiquitination of histone H2A. Moreover, UTX associates with mixed-lineage leukemia (MLL) 2/3 complexes, and during retinoic acid signaling events, the recruitment of the UTX complex to HOX genes results in H3K27 demethylation and a concomitant methylation of H3K4. Our results suggest a concerted mechanism for transcriptional activation in which cycles of H3K4 methylation by MLL2/3 are linked with the demethylation of H3K27 through UTX.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Differentiation
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Cell Line
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Cell Line, Tumor
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DNA-Binding Proteins / metabolism
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Embryonic Stem Cells
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Genes, Homeobox*
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Histone Demethylases
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Histones / metabolism*
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Humans
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Lysine / metabolism*
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Methylation
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Multigene Family
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Neoplasm Proteins / metabolism
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Polycomb-Group Proteins
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Promoter Regions, Genetic
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Protein Processing, Post-Translational
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Recombinant Proteins / metabolism
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Repressor Proteins / metabolism*
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Signal Transduction
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Transcription, Genetic
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Transcriptional Activation
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Tretinoin / metabolism
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Tretinoin / pharmacology
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Ubiquitin / metabolism
Substances
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DNA-Binding Proteins
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Histones
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KMT2C protein, human
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KMT2D protein, human
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Neoplasm Proteins
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Nuclear Proteins
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Polycomb-Group Proteins
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Recombinant Proteins
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Repressor Proteins
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Ubiquitin
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Tretinoin
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Histone Demethylases
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KDM6A protein, human
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Lysine