Demethylation of H3K27 Regulates Polycomb Recruitment and H2A Ubiquitination

• DOI: 10.1126/science.1149042
• Publication Date: 2007-08-31T01:15:10Z
• Authors: Min Gyu Lee; Raffaella Villa; Patrick Trojer; Jessica Norman; Kai-Ping Yan; Danny Reinberg; Luciano Di Croce; Ramin Shiekhattar
• Keywords: Histone Demethylases; 0301 basic medicine; Lysine; Genes, Homeobox; Nuclear Proteins; Polycomb-Group Proteins; Cell Differentiation; Methylation; Recombinant Proteins; Cell Line; Neoplasm Proteins; DNA-Binding Proteins; Histones; Repressor Proteins; 03 medical and health sciences; Cell Line, Tumor; Multigene Family; Humans; Promoter Regions, Genetic; Protein Processing, Post-Translational; Embryonic Stem Cells; Signal Transduction

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.