Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

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

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Kouzarides, T. Histone methylation in transcriptional control. Curr. Opin. Genet. Dev. 12, 198–209 (2002)

    Article  CAS  PubMed  Google Scholar 

  2. Bhaumik, S. R., Smith, E. & Shilatifard, A. Covalent modifications of histones during development and disease pathogenesis. Nature Struct. Mol. Biol. 14, 1008–1016 (2007)

    Article  CAS  Google Scholar 

  3. Lachner, M., O’Sullivan, R. J. & Jenuwein, T. An epigenetic road map for histone lysine methylation. J. Cell Sci. 116, 2117–2124 (2003)

    Article  CAS  PubMed  Google Scholar 

  4. Ruthenburg, A. J., Li, H., Patel, D. J. & Allis, C. D. Multivalent engagement of chromatin modifications by linked binding modules. Nature Rev. Mol. Cell Biol. 8, 983–994 (2007)

    Article  CAS  Google Scholar 

  5. Klose, R. J., Kallin, E. M. & Zhang, Y. JmjC-domain-containing proteins and histone demethylation. Nature Rev. Genet. 7, 715–727 (2006)

    Article  CAS  PubMed  Google Scholar 

  6. Heintzman, N. D. et al. Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature 459, 108–112 (2009)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  7. Mellor, J. It takes a PHD to read the histone code. Cell 126, 22–24 (2006)

    Article  CAS  PubMed  Google Scholar 

  8. Loenarz, C. et al. PHF8, a gene associated with cleft lip/palate and mental retardation, encodes for an Nε-dimethyl lysine demethylase. Hum. Mol. Genet. 19, 217–222 (2010)

    Article  CAS  PubMed  Google Scholar 

  9. Fortschegger, K. et al. PHF8 targets histone methylation and RNA polymerase II to activate transcription. Mol. Cell Biol. advance online publication, 10.1128/MCB.01520-09 (26 April 2010)

  10. Horton, J. R. et al. Enzymatic and structural insights for substrate specificity of a family of jumonji histone lysine demethylases. Nature Struct. Mol. Biol. 17, 38–43 (2010)

    Article  CAS  Google Scholar 

  11. Kleine-Kohlbrecher, D. et al. A functional link between the histone demethylase PHF8 and the transcription factor ZNF711 in X-linked mental retardation. Mol. Cell 38, 165–178 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Feng, W., Yonezawa, M., Ye, J., Jenuwein, T. & Grummt, I. PHF8 activates transcription of rRNA genes through H3K4me3 binding and H3K9me1/2 demethylation. Nature Struct. Mol. Biol. 17, 445–450 (2010)

    Article  CAS  Google Scholar 

  13. Jørgensen, S. et al. The histone methyltransferase SET8 is required for S-phase progression. J. Cell Biol. 179, 1337–1345 (2007)

    Article  PubMed  PubMed Central  Google Scholar 

  14. Tardat, M., Murr, R., Herceg, Z., Sardet, C. & Julien, E. PR-Set7-dependent lysine methylation ensures genome replication and stability through S phase. J. Cell Biol. 179, 1413–1426 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Houston, S. I. et al. Catalytic function of the PR-Set7 histone H4 lysine 20 monomethyltransferase is essential for mitotic entry and genomic stability. J. Biol. Chem. 283, 19478–19488 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yin, Y., Yu, V. C., Zhu, G. & Chang, D. C. SET8 plays a role in controlling G1/S transition by blocking lysine acetylation in histone through binding to H4 N-terminal tail. Cell Cycle 7, 1423–1432 (2008)

    Article  CAS  PubMed  Google Scholar 

  17. Oda, H. et al. Monomethylation of histone H4-lysine 20 is involved in chromosome structure and stability and is essential for mouse development. Mol. Cell. Biol. 29, 2278–2295 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tyagi, S., Chabes, A. L., Wysocka, J. & Herr, W. E2F activation of S phase promoters via association with HCF-1 and the MLL family of histone H3K4 methyltransferases. Mol. Cell 27, 107–119 (2007)

    Article  CAS  PubMed  Google Scholar 

  19. Wysocka, J., Myers, M. P., Laherty, C. D., Eisenman, R. N. & Herr, W. Human Sin3 deacetylase and trithorax-related Set1/Ash2 histone H3–K4 methyltransferase are tethered together selectively by the cell-proliferation factor HCF-1. Genes Dev. 17, 896–911 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Trojer, P. et al. L3MBTL1, a histone-methylation-dependent chromatin lock. Cell 129, 915–928 (2007)

    Article  CAS  PubMed  Google Scholar 

  21. Julien, E. & Herr, W. Proteolytic processing is necessary to separate and ensure proper cell growth and cytokinesis functions of HCF-1. EMBO J. 22, 2360–2369 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Losada, A. & Hirano, T. Dynamic molecular linkers of the genome: the first decade of SMC proteins. Genes Dev. 19, 1269–1287 (2005)

    Article  CAS  PubMed  Google Scholar 

  23. Hudson, D. F., Marshall, K. M. & Earnshaw, W. C. Condensin: architect of mitotic chromosomes. Chromosome Res. 17, 131–144 (2009)

    Article  CAS  PubMed  Google Scholar 

  24. Belmont, A. S. Mitotic chromosome structure and condensation. Curr. Opin. Cell Biol. 18, 632–638 (2006)

    Article  CAS  PubMed  Google Scholar 

  25. Haering, C. H. Foreword: the many fascinating functions of SMC protein complexes. Chromosome Res. 17, 127–129 (2009)

    Article  CAS  PubMed  Google Scholar 

  26. Wolf, F., Sigl, R. & Geley, S. '… The end of the beginning': cdk1 thresholds and exit from mitosis. Cell Cycle 6, 1408–1411 (2007)

    Article  CAS  PubMed  Google Scholar 

  27. Ono, T. et al. Differential contributions of condensin I and condensin II to mitotic chromosome architecture in vertebrate cells. Cell 115, 109–121 (2003)

    Article  CAS  PubMed  Google Scholar 

  28. Strahl, B. D. & Allis, C. D. The language of covalent histone modifications. Nature 403, 41–45 (2000)

    Article  ADS  CAS  PubMed  Google Scholar 

  29. Neuwald, A. F. & Hirano, T. HEAT repeats associated with condensins, cohesins, and other complexes involved in chromosome-related functions. Genome Res. 10, 1445–1452 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Andrade, M. A. & Bork, P. HEAT repeats in the Huntington’s disease protein. Nature Genet. 11, 115–116 (1995)

    Article  CAS  PubMed  Google Scholar 

  31. Garcia-Bassets, I. et al. Histone methylation-dependent mechanisms impose ligand dependency for gene activation by nuclear receptors. Cell 128, 505–518 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Langmead, B., Trapnell, C., Pop, M. & Salzberg, S. L. Ultrafast and memory efficient alignment of short DNA sequences to the human genome. Genome Biol. 10, R25 (2009)

    Article  PubMed  PubMed Central  Google Scholar 

  33. Zhang, Y. et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 9, R137 (2008)

    Article  PubMed  PubMed Central  Google Scholar 

  34. Zang, C. et al. A clustering approach for identification of enriched domains from histone modification ChIP-Seq data. Bioinformatics 25, 1952–1958 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Huang D. W, Sherman, B. T. & Lempicki, R. A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nature Protocols 4, 44–57 (2009)

    Article  Google Scholar 

  36. Maere, S., Heymans, K. & Kuiper, M. BiNGO: a Cytoscape plugin to assess overrepresentation of gene ontology categories in biological networks. Bioinformatics 21, 3448–3449 (2005)

    Article  CAS  PubMed  Google Scholar 

  37. Šášik, R., Woelk, C. H. & Corbeil, J. Microarray truths and consequences. J. Mol. Endocrinol. 33, 1–9 (2004)

    Article  PubMed  Google Scholar 

  38. Tusher, V. G., Tibshirani, R. & Chu, G. Significance analysis of microarrays applied to the ionizing radiation response. Proc. Natl Acad. Sci. USA 98, 5116–5121 (2001)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  39. Saeed, A. I. et al. TM4 microarray software suite. Methods Enzymol. 411, 134–193 (2006)

    Article  CAS  PubMed  Google Scholar 

  40. Schwender, H. & Ickstadt, K. Empirical Bayes analysis of single nucleotide polymorphisms. BMC Bioinformatics 9, 144 (2008)

    Article  PubMed  PubMed Central  Google Scholar 

  41. Tanner, S. et al. InsPecT: identification of posttranslationally modified peptides from tandem mass spectra. Anal. Chem. 77, 4626–4639 (2005)

    Article  CAS  PubMed  Google Scholar 

  42. Yeong, F. M. et al. Identification of a subunit of a novel Kleisin-β/SMC complex as a potential substrate of protein phosphatase 2A. Curr. Biol. 13, 2058–2064 (2003)

    Article  CAS  PubMed  Google Scholar 

Download references

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.

Author information

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

Authors
  1. Wen Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bogdan Tanasa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Oksana V. Tyurina
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tian Yuan Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Reto Gassmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wei Ting Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kenneth A. Ohgi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chris Benner
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ivan Garcia-Bassets
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Aneel K. Aggarwal
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Arshad Desai
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Pieter C. Dorrestein
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Christopher K. Glass
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Michael G. Rosenfeld
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding author

Correspondence to Michael G. Rosenfeld.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures S1-S18 with legends. (PDF 4649 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature09272

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing