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PHF8 mediates histone H4 lysine 20 demethylation events involved in cell cycle progression.
Open accessAbstract
While reversible histone modifications are linked to an ever-expanding range of biological functions, 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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“As we discussed in the Cell Cycle Regulation section, USP7 deubiquitinates and stabilizes PHF8, allowing the latter to upregulate gene targets involved in cell cycle progression, including cyclin A2 (Liu et al., 2010; Wang et al., 2016).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Liu et al., 2010
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Citations
Cites
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“Similar results were obtained with PHF8 (1-447) (Fig.”
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“The great majority of PHF8-bound promoters overlapped with H3K4me3 (6) and H3K4me2 positive promoters, while very few harbored H4K20me1, H3K9me1/2, or H3K27me2 marks (Fig.”
BackgroundResult[9] TM4 Microarray Software Suite
Saeed, A. I., BHAGABATI, N. K., Braisted, J. C., Liang, W. P., Sharov, V., Howe, E., Li, J., Thiagarajan, M., White, J., & Quackenbush, J. F. (2006) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(06)11009-5 · Cited by 1,996
JmjC-domain-containing proteins and histone demethylation
Klose, R. J., Kallin, E. M., & Zhang, Y. (2006) · Nature Reviews Genetics · doi:10.1038/nrg1945 · Cited by 1,290 · cited 1×
“A gradient for eluting trypsin-digested peptides was established with a time-varying solvent mixture ((min, % of solvent A): (15, 95), (50, 60), (70, 30), (75, 5)) and electrosprayed directly into the LTQ-MS inlet (source voltage, 1.”
MethodA clustering approach for identification of enriched domains from histone modification ChIP-Seq data
Zang, C., Schones, D. E., Zeng, C., Cui, K., Zhao, K., & Peng, W. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp340 · Cited by 1,072
Multivalent engagement of chromatin modifications by linked binding modules
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“Similar results were obtained with PHF8 (1-447) (Fig.”
ResultHistone methylation in transcriptional control
Kouzarides, T. (2002) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(02)00287-3 · Cited by 908 · cited 1×
“Full-length PHF8 or truncations were PCR-amplified from cDNA samples from HeLa cells by using KOD Hot Start Master mix (Novagen) and cloned into p3XFLAG-CMV-10 (Sigma), pET-28a(1) (Novagen) or pEGFP-C3 (Clontech) vectors.”
MethodCovalent modifications of histones during development and disease pathogenesis
Bhaumik, S. R., Smith, E. R., & Shilatifard, A. (2007) · Nature Structural & Molecular Biology · doi:10.1038/nsmb1337 · Cited by 704 · cited 1×
“Similar results were obtained with PHF8 (1-447) (Fig.”
ResultAn epigenetic road map for histone lysine methylation
Lachner, M., O’Sullivan, R. J., & Jenuwein, T. (2003) · Journal of Cell Science · doi:10.1242/jcs.00493 · Cited by 641 · cited 1×
“Similar results were obtained with PHF8 (1-447) (Fig.”
ResultHEAT repeats in the Huntington's disease protein
Andrade-Navarro, M. A., & Peer Bork, B. (1995) · Nature Genetics · doi:10.1038/ng1095-115 · Cited by 601
Ono, T., Losada, A., Hirano, M., Myers, M., Neuwald, A. F., & Hirano, T. (2003) · Cell · doi:10.1016/s0092-8674(03)00724-4 · Cited by 588 · cited 1×
“Similar results were obtained with PHF8 (1-447) (Fig.”
ResultInsPecT: Identification of Posttranslationally Modified Peptides from Tandem Mass Spectra
Tanner, S. W., Shu, H., Frank, A. M., Wang, L.-C., Zandi, E., Mumby, M. C., Pevzner, P. A., & Bafna, V. (2005) · Analytical Chemistry · doi:10.1021/ac050102d · Cited by 568
García-Bassets, I., Kwon, Y., Telese, F., Préfontaine, G. G., Hutt, K. R., Cheng, C. S., Ju, B., Ohgi, K. A., Wang, J., Escoubet‐Lozach, L., et al. (2007) · Cell · doi:10.1016/j.cell.2006.12.038 · Cited by 438
Self-citationWysocka, J., Myers, M. P., Laherty, C. D., Eisenman, R. N., & Herr, W. (2003) · Genes & Development · doi:10.1101/gad.252103 · Cited by 391 · cited 1×
“Similar results were obtained with PHF8 (1-447) (Fig.”
ResultHorton, J. R., Upadhyay, A. K., Qi, H. H., Zhang, X., Shi, Y., & Cheng, X. (2010) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1753 · Cited by 389 · cited 1×
“Similar results were obtained with PHF8 (1-447) (Fig.”
ResultDynamic molecular linkers of the genome: the first decade of SMC proteinsPreprint
Losada, A., & Hirano, T. (2005) · Genes & Development · doi:10.1101/gad.1320505 · Cited by 368 · cited 1×
“Similar results were obtained with PHF8 (1-447) (Fig.”
ResultL3MBTL1, a Histone-Methylation-Dependent Chromatin Lock
Trojer, P., Li, G., Sims, R. J., Vaquero, A., Kalakonda, N., Boccuni, P., Lee, D., Erdjument‐Bromage, H., Tempst, P., Nimer, S. D., et al. (2007) · Cell · doi:10.1016/j.cell.2007.03.048 · Cited by 360 · cited 1×
“Similar results were obtained with PHF8 (1-447) (Fig.”
ResultOda, H., Okamoto, I., Murphy, N., Chu, J., Price, S. M., Shen, M. M., Torres-Padilla, M. E., Heard, É., & Reinberg, D. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.01768-08 · Cited by 319 · cited 1×
“Similar results were obtained with PHF8 (1-447) (Fig.”
ResultNeuwald, A. F., & Hirano, T. (2000) · Genome Research · doi:10.1101/gr.147400 · Cited by 284 · cited 1×
“Similar results were obtained with PHF8 (1-447) (Fig.”
ResultTyagi, S., Chabes, A. L., Wysocka, J., & Herr, W. (2007) · Molecular Cell · doi:10.1016/j.molcel.2007.05.030 · Cited by 254 · cited 1×
“Similar results were obtained with PHF8 (1-447) (Fig.”
ResultThe histone methyltransferase SET8 is required for S-phase progression
Jørgensen, S., Elvers, I., Trelle, M. B., Menzel, T., Eskildsen, M., Jensen, O. N., Helleday, T., Helin, K., & Sørensen, C. S. (2007) · The Journal of Cell Biology · doi:10.1083/jcb.200706150 · Cited by 225 · cited 1×
“Similar results were obtained with PHF8 (1-447) (Fig.”
ResultPHF8 activates transcription of rRNA genes through H3K4me3 binding and H3K9me1/2 demethylation
Feng, W., Yonezawa, M., Ye, J., Jenuwein, T., & Grummt, I. (2010) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1778 · Cited by 224 · cited 1×
“Similar results were obtained with PHF8 (1-447) (Fig.”
ResultIt Takes a PHD to Read the Histone Code
Mellor, J. (2006) · Cell · doi:10.1016/j.cell.2006.06.028 · Cited by 217 · cited 1×
“Similar results were obtained with PHF8 (1-447) (Fig.”
ResultKleine‐Kohlbrecher, D., Christensen, J. F., Vandamme, J., Abarrategui, I., Bak, M., Tommerup, N., Shi, X., Gozani, O., Rappsilber, J., Salcini, A. E., et al. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.03.002 · Cited by 212 · cited 1×
“Similar results were obtained with PHF8 (1-447) (Fig.”
Mitotic chromosome structure and condensation
Belmont, A. S. (2006) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2006.09.007 · Cited by 192 · cited 1×
“Similar results were obtained with PHF8 (1-447) (Fig.”
ResultPR-Set7–dependent lysine methylation ensures genome replication and stability through S phase
Tardat, M., Murr, R., Herceg, Z., Sardet, C., & Julien, E. (2007) · The Journal of Cell Biology · doi:10.1083/jcb.200706179 · Cited by 175 · cited 1×
“12% (14,508) H4K20me1 ChIP-Seq (M phase) me3 me2 me1 In p ut”
Loenarz, C., Ge, W., Coleman, M. L., Rose, N. R., Cooper, C. D. O., Klose, R. J., Ratcliffe, P. J., & Schofield, C. J. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp480 · Cited by 171
Houston, S. I., McManus, K. J., Adams, M. M., Sims, J. K., Carpenter, P. B., Hendzel, M. J., & Rice, J. C. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m710579200 · Cited by 154 · cited 1×
“A gradient for eluting trypsin-digested peptides was established with a time-varying solvent mixture ((min, % of solvent A): (15, 95), (50, 60), (70, 30), (75, 5)) and electrosprayed directly into the LTQ-MS inlet (source voltage, 1.”
MethodJulien, E., & Herr, W. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg242 · Cited by 131 · cited 1×
“Similar results were obtained with PHF8 (1-447) (Fig.”
ResultCondensin: Architect of mitotic chromosomes
Hudson, D. F., Marshall, K. M., & Earnshaw, W. C. (2009) · Chromosome Research · doi:10.1007/s10577-008-9009-7 · Cited by 128 · cited 1×
“Similar results were obtained with PHF8 (1-447) (Fig.”
ResultPHF8 Targets Histone Methylation and RNA Polymerase II To Activate Transcription
Fortschegger, K., de Graaf, P., Outchkourov, N. S., van Schaik, F. M. A., Timmers, H. T. M., & Shiekhattar, R. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.01520-09 · Cited by 119
Yeong, F. M., Hombauer, H., Wendt, K. S., Hirota, T., Mudrak, I., Mechtler, K., Loregger, T., Marchler‐Bauer, A., Tanaka, K., Peters, J., et al. (2003) · Current Biology · doi:10.1016/j.cub.2003.10.032 · Cited by 94
Microarray truths and consequences
Sasik, R., Woelk, C., & Corbeil, J. (2004) · Journal of Molecular Endocrinology · doi:10.1677/jme.0.0330001 · Cited by 73
Yin, Y., Yu, V. C. K., Zhu, G., & Chang, D. C. (2008) · Cell Cycle · doi:10.4161/cc.7.10.5867 · Cited by 61
‘… The End of the Beginning’: Cdk1 Thresholds and Exit from Mitosis
Wolf, F., Sigl, R., & Geley, S. (2007) · Cell Cycle · doi:10.4161/cc.6.12.4361 · Cited by 41 · cited 1×
“Similar results were obtained with PHF8 (1-447) (Fig.”
ResultEmpirical Bayes analysis of single nucleotide polymorphisms
Schwender, H., & Ickstadt, K. (2008) · BMC Bioinformatics · doi:10.1186/1471-2105-9-144 · Cited by 24
Foreword: the many fascinating functions of SMC protein complexes
Haering, C. H. (2009) · Chromosome Research · doi:10.1007/s10577-008-9008-8 · Cited by 3 · cited 1×
“Similar results were obtained with PHF8 (1-447) (Fig.”
Result
Cited by
Sorted by citations
Histone methylation: a dynamic mark in health, disease and inheritance
Greer, E. L., & Shi, Y. (2012) · Nature Reviews Genetics · doi:10.1038/nrg3173 · Cited by 2,241
Histone Lysine Methylation Dynamics: Establishment, Regulation, and Biological Impact
Black, J. C., Rechem, C. V., & Whetstine, J. R. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.11.006 · Cited by 1,391
“Similarly, the KDM7B (PHF8) demethylase is regulated over cell cycle with peak levels in G1/S, which corresponds to the role of KDM7B in regulating E2F1 targets and G1/S transition (Figure 3) (Liu et al., 2010).”
Writing, erasing and reading histone lysine methylations
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lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs
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“ChIP assays and ChIP-Seq was performed as described 28 .”
Self-citation
Metadata
- Authors
- Liu, W., Tanasa, B., Tyurina, O. V., Zhou, T. Y., Gassmann, R., Liu, W. T., Ohgi, K. A., Benner, C., Garcia-Bassets, I., Aggarwal, A. K., Desai, A., Dorrestein, P. C., Glass, C. K., & Rosenfeld, M. G.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of California San Diego (US)
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Rosenfeld, Michael G.
- ORCID
- Venue
- Nature
- Published
- 2010-07
- Volume
- 466
- Issue
- 7305
- Pages
- 508-512
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3059551
- OpenAlex
- W2130239280
- Cited by
- 441
- References
- 43
- Citations by year
- 2026: 10 · 2025: 19 · 2024: 17 · 2023: 39 · 2022: 21 · 2021: 37 · 2020: 16 · 2019: 17 · 2018: 19 · 2017: 35 · 2016: 32 · 2015: 30 · 2014: 33 · 2013: 39 · 2012: 33
- FWCI
- 15.23
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- U.S. Department of Defense
- Howard Hughes Medical Institute
- National Institutes of Health
- University of California, San Diego
- National Heart, Lung, and Blood Institute (R01HL065445)
- National Cancer Institute (R01CA097134)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK039949, R37DK039949, R01DK018477)
- National Institute of Neurological Disorders and Stroke (R01NS034934)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
- Keywords
- PHF8, H4K20me1, Jumonji C domain, cell cycle progression, G1/S transition, E2F1, HCF-1, SET1A, X-linked intellectual disability, craniofacial development, neuronal survival, histone demethylase, chromatin regulation, zebrafish, promoter recruitment
- MeSH terms
- Adenosine Triphosphatases, Cell Cycle, Cell Line, Chromatin, Chromosomal Proteins, Non-Histone, DNA-Binding Proteins, HeLa Cells, Histones, Humans, Lysine, Methylation, Phosphorylation, Promoter Regions, Genetic, Histone-Lysine N-Methyltransferase, Transcription Factors, Protein Structure, Tertiary, Multiprotein Complexes, Host Cell Factor C1, Histone Demethylases
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