Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination.
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.
Lee
Min Gyu
MG
Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.
Villa
Raffaella
R
Trojer
Patrick
P
Norman
Jessica
J
Yan
Kai-Ping
KP
Reinberg
Danny
D
Di Croce
Luciano
L
Shiekhattar
Ramin
R
D002454:Cell Differentiation; D002460:Cell Line; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D053595:Embryonic Stem Cells; D005801:Genes, Homeobox; D056466:Histone Demethylases; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D008745:Methylation; D005810:Multigene Family; D009363:Neoplasm Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D063146:Polycomb-Group Proteins; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D011994:Recombinant Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology; D025801:Ubiquitin / Q000378:metabolism
D004268:DNA-Binding Proteins; D006657:Histones; C452979:KMT2C protein, human; C120898:KMT2D protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D063146:Polycomb-Group Proteins; D011994:Recombinant Proteins; D012097:Repressor Proteins; D025801:Ubiquitin; D014212:Tretinoin; D056466:Histone Demethylases; C523998:KDM6A protein, human; D008239:Lysine