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PHF8 mediates histone H4 lysine 20 demethylation events involved in cell cycle progression

Nature volume 466, pages 508–512 (2010)Cite this article

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Abstract

While reversible histone modifications are linked to an ever-expanding range of biological functions1,2,3,4,5, the demethylases for histone H4 lysine 20 and their potential regulatory roles remain unknown. Here we report that the PHD and Jumonji C (JmjC) domain-containing protein, PHF8, while using multiple substrates, including H3K9me1/2 and H3K27me2, also functions as an H4K20me1 demethylase. PHF8 is recruited to promoters by its PHD domain based on interaction with H3K4me2/3 and controls G1–S transition in conjunction with E2F1, HCF-1 (also known as HCFC1) and SET1A (also known as SETD1A), at least in part, by removing the repressive H4K20me1 mark from a subset of E2F1-regulated gene promoters. Phosphorylation-dependent PHF8 dismissal from chromatin in prophase is apparently required for the accumulation of H4K20me1 during early mitosis, which might represent a component of the condensin II loading process. Accordingly, the HEAT repeat clusters in two non-structural maintenance of chromosomes (SMC) condensin II subunits, N-CAPD3 and N-CAPG2 (also known as NCAPD3 and NCAPG2, respectively), are capable of recognizing H4K20me1, and ChIP-Seq analysis demonstrates a significant overlap of condensin II and H4K20me1 sites in mitotic HeLa cells. Thus, the identification and characterization of an H4K20me1 demethylase, PHF8, has revealed an intimate link between this enzyme and two distinct events in cell cycle progression.

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Figure 1: Histone demethylation mediated by PHF8.
Figure 2: Characterization of PHF8 protein.
Figure 3: PHF8 regulates E2F target genes in conjunction with HCF-1 and SET1A during G1–S transition.
Figure 4: Phosphorylation-dependent PHF8 dissociation from chromatin in prophase links H4K20me1 with condensin II.

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Acknowledgements

We thank W. Herr for providing HCF-1 and SET1A antibody; A. C. Wilson for providing pCGN-GAL4-HA-HCF-1(N1011) and pCGN-GAL4-HA-HCF-1(C600) expression vectors; A. I. Lamond for providing YFP-HCF-1 expression vector; K. Wang for experimental assistance; J. Nand for assistance with the ChIP-Seq data analysis; C. Nelson for cell culture assistance; J. Hightower and D. Benson for assistance with figure and manuscript preparation and the UCSD BIOGEM laboratory for RNA profiling. M.G.R. is an Investigator with the Howard Hughes Medical Institute. This work was supported by grants from NIH and NCI to A.K.A., P.C.D., C.K.G, A.D. and M.G.R. and from DOD and PCF to M.G.R. We apologize that we were not able to cite all the studies in the primary references characterizing PHF8 family enzymatic activities while our work was under review, due to reference limitation.

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Authors and Affiliations

  1. Howard Hughes Medical Institute, School of Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA ,

    Wen Liu, Bogdan Tanasa, Oksana V. Tyurina, Tian Yuan Zhou, Kenneth A. Ohgi, Ivan Garcia-Bassets & Michael G. Rosenfeld

  2. Graduate Program in Biology, University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA ,

    Wen Liu

  3. Kellogg School of Science and Technology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA ,

    Bogdan Tanasa

  4. Ludwig Institute for Cancer Research/ Department of Cellular and Molecular Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA,

    Reto Gassmann & Arshad Desai

  5. Skaggs School of Pharmacy and Pharmaceutical Sciences/Department of Chemistry and Biochemistry, University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA,

    Wei Ting Liu & Pieter C. Dorrestein

  6. Department of Cellular and Molecular Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA,

    Chris Benner & Christopher K. Glass

  7. Department of Structural and Chemical Biology, Mount Sinai School of Medicine, Box 1677, 1425 Madison Avenue, New York, New York 10029, USA,

    Aneel K. Aggarwal

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Contributions

W.L. and M.G.R. designed the experiments and W.L. performed most of the experiments. W.L. and M.G.R. prepared the manuscript with contributions of I.G.-B., A.K.A., A.D., P.C.D. and C.K.G.; B.T. and C.B. analysed the ChIP-Seq and microarray data. T.Y.Z and K.A.O generated Flag–PHF8 constructs. W.T.L. helped with mass spectrometry analysis. R.G. and O.V.T. performed confocal microscopy in mitosis. I.G.-B performed gel filtration chromatograph.

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Correspondence to Michael G. Rosenfeld.

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Liu, W., Tanasa, B., Tyurina, O. et al. PHF8 mediates histone H4 lysine 20 demethylation events involved in cell cycle progression. Nature 466, 508–512 (2010). https://doi.org/10.1038/nature09272

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