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PHF8 targets histone methylation and RNA polymerase II to activate transcription.
Fortschegger, Klaus; de Graaf, Petra; Outchkourov, Nikolay S; van Schaik, Frederik M A; Timmers, H T Marc; Shiekhattar, Ramin.
Afiliación
  • Fortschegger K; Center for Genomic Regulation, Barcelona Biomedical Research Park, 08003 Barcelona, Spain.
Mol Cell Biol ; 30(13): 3286-98, 2010 Jul.
Article en En | MEDLINE | ID: mdl-20421419
Mutations in PHF8 are associated with X-linked mental retardation and cleft lip/cleft palate. PHF8 contains a plant homeodomain (PHD) in its N terminus and is a member of a family of JmjC domain-containing proteins. While PHDs can act as methyl lysine recognition motifs, JmjC domains can catalyze lysine demethylation. Here, we show that PHF8 is a histone demethylase that removes repressive histone H3 dimethyl lysine 9 marks. Our biochemical analysis revealed specific association of the PHF8 PHD with histone H3 trimethylated at lysine 4 (H3K4me3). Chromatin immunoprecipitation followed by high-throughput sequencing indicated that PHF8 is enriched at the transcription start sites of many active or poised genes, mirroring the presence of RNA polymerase II (RNAPII) and of H3K4me3-bearing nucleosomes. We show that PHF8 can act as a transcriptional coactivator and that its activation function largely depends on binding of the PHD to H3K4me3. Furthermore, we present evidence for direct interaction of PHF8 with the C-terminal domain of RNAPII. Importantly, a PHF8 disease mutant was defective in demethylation and in coactivation. This is the first demonstration of a chromatin-modifying enzyme that is globally recruited to promoters through its association with H3K4me3 and RNAPII.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Transcripción / ARN Polimerasa II / Histonas / Histona Demetilasas Límite: Humans Idioma: En Revista: Mol Cell Biol Año: 2010 Tipo del documento: Article País de afiliación: España Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Transcripción / ARN Polimerasa II / Histonas / Histona Demetilasas Límite: Humans Idioma: En Revista: Mol Cell Biol Año: 2010 Tipo del documento: Article País de afiliación: España Pais de publicación: Estados Unidos