Systematic name M2487
Brief description Genes up-regulated in HeLa cells (cervical carcinoma) upon knockdown of PHF8 [GeneID=23133] by RNAi.
Full description or abstract 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.
Collection C2: Curated
      CGP: Chemical and Genetic Perturbations
Source publication Pubmed 20421419   Authors: Fortschegger K,de Graaf P,Outchkourov NS,van Schaik FM,Timmers HT,Shiekhattar R
Exact source Table 3S: sheet: Upregulated
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Source species Homo sapiens
Contributed by Arthur Liberzon (MSigDB Team)
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NCI-60 cell lines (National Cancer Institute)
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Version history 3.1: First introduced

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