PHF8 targets histone methylation and RNA polymerase II to activate transcription

Klaus Fortschegger, Petra De Graaf, Nikolay S. Outchkourov, Frederik M.A. Van Schaik, H. T. Marc Timmers, Ramin Shiekhattar

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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.

Original languageEnglish (US)
Pages (from-to)3286-3298
Number of pages13
JournalMolecular and cellular biology
Volume30
Issue number13
DOIs
StatePublished - Jul 1 2010

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Fortschegger, K., De Graaf, P., Outchkourov, N. S., Van Schaik, F. M. A., Marc Timmers, H. T., & Shiekhattar, R. (2010). PHF8 targets histone methylation and RNA polymerase II to activate transcription. Molecular and cellular biology, 30(13), 3286-3298. https://doi.org/10.1128/MCB.01520-09