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PHF8 activates transcription of rRNA genes through H3K4me3 binding and H3K9me1/2 demethylation

Nature Structural & Molecular Biology volume 17, pages 445–450 (2010)Cite this article

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Abstract

Histone lysine methylation is dynamically regulated by lysine methyltransferases and lysine demethylases. Here we show that PHD finger protein 8 (PHF8), a protein containing a PHD finger and a Jumonji C (JmjC) domain, is associated with hypomethylated rRNA genes (rDNA). PHF8 interacts with the RNA polymerase I transcription machinery and with WD repeat–containing protein 5 (WDR5)-containing H3K4 methyltransferase complexes. PHF8 exerts a positive effect on rDNA transcription, with transcriptional activation requiring both the JmjC domain and the PHD finger. PHF8 demethylates H3K9me1/2, and its catalytic activity is stimulated by adjacent H3K4me3. A point mutation within the JmjC domain that is linked to mental retardation with cleft lip and palate (XLMR-CL/P) abolishes demethylase activity and transcriptional activation. Though further work is needed to unravel the contribution of PHF8 activity to mental retardation and cleft lip/palate, our results reveal a functional interplay between H3K4 methylation and H3K9me1/2 demethylation, linking dynamic histone methylation to rDNA transcription and neural disease.

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Figure 1: PHF8 localizes within nucleoli and binds to rDNA.
Figure 2: PHF8 is required for efficient Pol I transcription in vivo.
Figure 3: Association with H3K4me3 is required for PHF8 function.
Figure 4: Demethylation of H3K9me1/2 is stimulated by adjacent H3K4me3.

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Acknowledgements

We thank A. Schmidt and K. Mechtler from the Research Institute of Molecular Pathology Protein Chemistry Facility for support in MS, U. Hoffmann-Rohrer (DKFZ) for bisulfite sequencing and W. Herr (Center for Integrative Genomics) for antibodies against WDR5 and Ash2L. Work in the laboratory of I.G. was funded by the DKFZ, the Deutsche Forschungsgemeinschaft (SFB/Transregio 5, SP, Epigenetics), the EU Network 'The Epigenome' and the Fonds der Chemischen Industrie. Research in the laboratory of T.J. was sponsored by Boehringer Ingelheim and the EU Network 'The Epigenome' (LSHG-CT-2004-503433).

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Author notes

  1. Masato Yonezawa & Thomas Jenuwein

    Present address: Present address: Max Planck Institute of Immunobiology, Freiburg, Germany.,

  2. Weijun Feng and Masato Yonezawa: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Molecular Biology of the Cell II, German Cancer Research Center, DKFZ-ZMBH Alliance, Heidelberg, Germany

    Weijun Feng, Jing Ye & Ingrid Grummt

  2. Research Institute of Molecular Pathology, The Vienna Biocenter, Vienna, Austria

    Masato Yonezawa & Thomas Jenuwein

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  1. Weijun Feng
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Contributions

W.F., M.Y. and J.Y. performed experiments; T.J. provided reagents and advice; all authors discussed the results and contributed to the writing of and commented on the manuscript; I.G. designed the project and wrote the manuscript.

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Correspondence to Ingrid Grummt.

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Feng, W., Yonezawa, M., Ye, J. et al. PHF8 activates transcription of rRNA genes through H3K4me3 binding and H3K9me1/2 demethylation. Nat Struct Mol Biol 17, 445–450 (2010). https://doi.org/10.1038/nsmb.1778

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