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Histone H4K20/H3K9 demethylase PHF8 regulates zebrafish brain and craniofacial development

Naturevolume 466, pages503–507 (2010)Cite this article

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Abstract

X-linked mental retardation (XLMR) is a complex human disease that causes intellectual disability1. Causal mutations have been found in approximately 90 X-linked genes2; however, molecular and biological functions of many of these genetically defined XLMR genes remain unknown. PHF8 (PHD (plant homeo domain) finger protein 8) is a JmjC domain-containing protein and its mutations have been found in patients with XLMR and craniofacial deformities. Here we provide multiple lines of evidence establishing PHF8 as the first mono-methyl histone H4 lysine 20 (H4K20me1) demethylase, with additional activities towards histone H3K9me1 and me2. PHF8 is located around the transcription start sites (TSS) of∼7,000 RefSeq genes and in gene bodies and intergenic regions (non-TSS). PHF8 depletion resulted in upregulation of H4K20me1 and H3K9me1 at the TSS and H3K9me2 in the non-TSS sites, respectively, demonstrating differential substrate specificities at different target locations. PHF8 positively regulates gene expression, which is dependent on its H3K4me3-binding PHD and catalytic domains. Importantly, patient mutations significantly compromised PHF8 catalytic function. PHF8 regulates cell survival in the zebrafish brain and jaw development, thus providing a potentially relevant biological context for understanding the clinical symptoms associated with PHF8 patients. Lastly, genetic and molecular evidence supports a model whereby PHF8 regulates zebrafish neuronal cell survival and jaw development in part by directly regulating the expression of the homeodomain transcription factor MSX1/MSXB, which functions downstream of multiple signalling and developmental pathways3. Our findings indicate that an imbalance of histone methylation dynamics has a critical role in XLMR.

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Figure 1:PHF8 and KIA1718 demethylate multiple lysines of histone 3 and 4in vitro.
Figure 2:PHF8 differently regulates H4K20me1, H3K9me1 and H3K9me2.
Figure 3:Depletion of PHF8 increasesH3K9me1,H4K20me1 andL3MBTL1 expression at TSS-bound PHF8 target genes.
Figure 4:zPHF8 regulates brain and craniofacial development in part through regulation ofmsxb.

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Gene Expression Omnibus

Data deposits

Genome-wide mapping data of PHF8, H4K20me1, H3K9me1, 2 and gene expression microarray analysis in HeLa cells reported in this paper are available at the Gene Expression Omnibus server (http://www.ncbi.nlm.nih.gov/geo/) with the accession numbersGSE21108 andGSE21555, respectively.

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Acknowledgements

We thank Shi laboratory members for helpful discussions and N. Mosammaparast and S. Chen for providing the nucleosomes. We thank G. Rosenfeld for sharing unpublished PHF8 results, and G. Rosenfeld, A. Schier and P. Hinds for discussions. H.H.Q. is a recipient of Ruth L. Kirschstein-National Service Research Award (T32 NS007473 and T32 CA09031-32). N.K.Y. was supported by Harvard SHURP (Summer Honors Undergraduate Research Program). H.L. is a recipient of the Agency for Science, Technology and Research (A*STAR) National Science Scholarship. This work was supported by grants from the National Science Foundation (CBET-0941143) to B.A.G.; NIH (GM 071004 and NCI118487) to Y.S.; a Senior Scholar Grant from the Ellison Foundation, and an NIH PO1 grant (CA50661) to T.M.R.

Author information

Author notes

  1. Madathia Sarkissian, Fei Lan, Maite Huarte & Nasser K. Yaghi

    Present address: Present addresses: Constellation Pharmaceuticals, 148 Sidney Street, Cambridge, Massachusetts 02139, USA (M.S.; F.L.); Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA (M.H.); Department of Biology, Texas A&M University, College Station, Texas 77843, USA (N.K.Y.).,

  2. Hank H. Qi and Madathia Sarkissian: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Hank H. Qi, Fei Lan, Maite Huarte, Nasser K. Yaghi, Huijun Lim & Yang Shi

  2. Division of Newborn Medicine, Department of Medicine, Children’s Hospital, Boston, 02115, Massachusetts, USA

    Hank H. Qi, Huijun Lim & Yang Shi

  3. Department of Cancer Biology, Dana Farber Cancer Institute, Boston, 02115, Massachusetts, USA

    Madathia Sarkissian & Thomas M. Roberts

  4. Laboratory of Molecular Immunology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Gang-Qing Hu, Zhibin Wang & Keji Zhao

  5. Agilent Technologies, 5301 Stevens Creek Boulevard, Santa Clara, 95051-8059, California, USA

    Arindam Bhattacharjee, D. Benjamin Gordon & Leonardo Brizuela

  6. Department of Molecular Biology, Princeton University, Princeton, 08544, New Jersey, USA

    Michelle Gonzales & Benjamin A. Garcia

  7. Vascular Medicine Research Unit, Brigham and Women's Hospital and Harvard Medical School, Boston, 02139, Massachusetts, USA

    Pat P. Ongusaha

Authors
  1. Hank H. Qi
  2. Madathia Sarkissian
  3. Gang-Qing Hu
  4. Zhibin Wang
  5. Arindam Bhattacharjee
  6. D. Benjamin Gordon
  7. Michelle Gonzales
  8. Fei Lan
  9. Pat P. Ongusaha
  10. Maite Huarte
  11. Nasser K. Yaghi
  12. Huijun Lim
  13. Benjamin A. Garcia
  14. Leonardo Brizuela
  15. Keji Zhao
  16. Thomas M. Roberts
  17. Yang Shi

Contributions

Y.S. and H.H.Q. conceived, designed the study, and co-wrote the manuscript. H.H.Q. performed cloning, demethylation,PHF8 knockdown, conventional ChIP, gene expression, cell cycle analysis and histone profiling experiments. T.M.R. directed the zebrafish work and M.S. performed zebrafish experiments; both T.M.R. and M.S. contributed to the writing of the manuscript. Z.W. performed the ChIP-Seq experiments; G.-Q.H. analysed the ChIP-Seq data; K.Z. directed the ChIP-Seq analysis; Z.W. and G.-Q.H. contributed equally to ChIP-Seq experiments. A.B., D.B.G. and L.B. contributed to the ChIP-chip experiments and data analysis. M.G. and B.A.G. performed mass spectrometry experiments and data analysis. F.L. identified that the PHD domain of PHF8 and KIAA1718 bind to H3K4me3. P.P.O. designed and helped in the cell cycle work. M.H. cloned the full-lengthKIAA1718 cDNA. N.K.Y. generated mutations in the PHD domain of PHF8 and H.L. helped in the demethylation assays.

Corresponding authors

Correspondence toThomas M. Roberts orYang Shi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-15 with legends and Supplementary Tables 1, 2, 5, 7, 8 and 9 (see separate files for Supplementary Tables 3, 4 and 6). (PDF 1668 kb)

Supplementary Table 3

This table contains ChIP-seq results of PHF8 binding events around TSS. (XLS 1638 kb)

Supplementary Table 4

This table contains ChIP-chip results of PHF8 binding events around TSS. (XLS 283 kb)

Supplementary Table 6

This table contains gene expression microarray data (Phalanx) from HeLa cells and IPA Analysis. (XLS 272 kb)

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Qi, H., Sarkissian, M., Hu, GQ.et al. Histone H4K20/H3K9 demethylase PHF8 regulates zebrafish brain and craniofacial development.Nature466, 503–507 (2010). https://doi.org/10.1038/nature09261

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Editorial Summary

Histone demethylase activity of PHF8

Mutations in thePHF8 gene, which encodes the plant homeo domain (PHD) finger protein 8, are connected to X-linked mental retardation associated with cleft lip and cleft palate. Two groups now report that the PHF8 protein is a histone demethylase with activity against H4K20me1 (histone H4 lysine 20). Qiet al. report a role for PHF8 in regulating gene expression, as well as in neuronal cell survival and craniofacial development in zebrafish. The results suggest there may be a link between histone methylation dynamics and X-linked mental retardation. Liuet al. show that PHF8 is linked to two distinct events during cell-cycle progression. PHF8 is recruited to the promoters of G1/S-phase genes where it removes H4K20me1 and contributes to gene activation, whereas dissociation of PHF8 from chromatin in prophase allows H4K20me1 to accumulate during mitosis.

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