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.

  • Original Article
  • Published:

Histone H4 lysine 20 monomethylation promotes transcriptional repression by L3MBTL1

Abstract

Lethal 3 malignant brain tumor 1 (L3MBTL1), a homolog of the Drosophila polycomb tumor suppressor l(3)mbt, contains three tandem MBT repeats (3xMBT) that are critical for transcriptional repression. We recently reported that the 3xMBT repeats interact with mono- and dimethylated lysines in the amino termini of histones H4 and H1b to promote methylation-dependent chromatin compaction. Using a series of histone peptides, we now show that the recognition of mono- and dimethylated lysines in histones H3, H4 and H1.4 (but not their trimethylated or unmodified counterparts) by 3xMBT occurs in the context of a basic environment, requiring a conserved aspartic acid (D355) in the second MBT repeat. Despite the broad range of in vitro binding, the chromatin association of L3MBTL1 mirrors the progressive accumulation of H4K20 monomethylation during the cell cycle. Furthermore, transcriptional repression by L3MBTL1 is enhanced by the H4K20 monomethyltransferase PR-SET7 (to which it binds) but not SUV420H1 (an H4K20 trimethylase) or G9a (an H3K9 dimethylase) and knockdown of PR-SET7 decreases H4K20me1 levels and the chromatin association of L3MBTL1. Our studies identify the importance of H4K20 monomethylation and of PR-SET7 for L3MBTL1 function.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Bannister AJ, Zegerman P, Partridge JF, Miska EA, Thomas JO, Allshire RC et al. (2001). Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature 410: 120–124.

    Article  CAS  Google Scholar 

  • Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z et al. (2007). High-resolution profiling of histone methylations in the human genome. Cell 129: 823–837.

    Article  CAS  Google Scholar 

  • Boccuni P, MacGrogan D, Scandura JM, Nimer SD . (2003). The human L(3)MBT polycomb group protein is a transcriptional repressor and interacts physically and functionally with TEL (ETV6). J Biol Chem 278: 15412–15420.

    Article  CAS  Google Scholar 

  • Bornemann D, Miller E, Simon J . (1998). Expression and properties of wild-type and mutant forms of the Drosophila sex comb on midleg (SCM) repressor protein. Genetics 150: 675–686.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Botuyan MV, Lee J, Ward IM, Kim JE, Thompson JR, Chen J et al. (2006). Structural basis for the methylation state-specific recognition of histone H4-K20 by 53BP1 and Crb2 in DNA repair. Cell 127: 1361–1373.

    Article  CAS  Google Scholar 

  • Dialynas GK, Terjung S, Brown JP, Aucott RL, Baron-Luhr B, Singh PB et al. (2007). Plasticity of HP1 proteins in mammalian cells. J Cell Sci 120: 3415–3424.

    Article  CAS  Google Scholar 

  • Fang J, Feng Q, Ketel CS, Wang H, Cao R, Xia L et al. (2002). Purification and functional characterization of SET8, a nucleosomal histone H4-lysine 20-specific methyltransferase. Curr Biol 12: 1086–1099.

    Article  CAS  Google Scholar 

  • Flanagan JF, Mi LZ, Chruszcz M, Cymborowski M, Clines KL, Kim Y et al. (2005). Double chromodomains cooperate to recognize the methylated histone H3 tail. Nature 438: 1181–1185.

    Article  CAS  Google Scholar 

  • Gateff E, Loffler T, Wismar J . (1993). A temperature-sensitive brain tumor suppressor mutation of Drosophila melanogaster: developmental studies and molecular localization of the gene. Mech Dev 41: 15–31.

    Article  CAS  Google Scholar 

  • Huang Y, Fang J, Bedford MT, Zhang Y, Xu RM . (2006). Recognition of histone H3 lysine-4 methylation by the double tudor domain of JMJD2A. Science 312: 748–751.

    Article  CAS  Google Scholar 

  • Huebert DJ, Bernstein BE . (2005). Genomic views of chromatin. Curr Opin Genet Dev 15: 476–481.

    Article  CAS  Google Scholar 

  • Ishizuka T, Lazar MA . (2003). The N-CoR/histone deacetylase 3 complex is required for repression by thyroid hormone receptor. Mol Cell Biol 23: 5122–5131.

    Article  CAS  Google Scholar 

  • Jacobs SA, Fischle W, Khorasanizadeh S . (2004). Assays for the determination of structure and dynamics of the interaction of the chromodomain with histone peptides. Methods Enzymol 376: 131–148.

    Article  CAS  Google Scholar 

  • Jacobs SA, Khorasanizadeh S . (2002). Structure of HP1 chromodomain bound to a lysine 9-methylated histone H3 tail. Science 295: 2080–2083.

    Article  CAS  Google Scholar 

  • Jorgensen S, Elvers I, Trelle MB, Menzel T, Eskildsen M, Jensen ON et al. (2007). The histone methyltransferase SET8 is required for S-phase progression. J Cell Biol 179: 1337–1345.

    Article  Google Scholar 

  • Julien E, Herr W . (2004). A switch in mitotic histone H4 lysine 20 methylation status is linked to M phase defects upon loss of HCF-1. Mol Cell 14: 713–725.

    Article  CAS  Google Scholar 

  • Karachentsev D, Sarma K, Reinberg D, Steward R . (2005). PR-Set7-dependent methylation of histone H4 Lys 20 functions in repression of gene expression and is essential for mitosis. Genes Dev 19: 431–435.

    Article  CAS  Google Scholar 

  • Kim J, Daniel J, Espejo A, Lake A, Krishna M, Xia L et al. (2006). Tudor, MBT and chromo domains gauge the degree of lysine methylation. EMBO Rep 7: 397–403.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Klymenko T, Papp B, Fischle W, Kocher T, Schelder M, Fritsch C et al. (2006). A Polycomb group protein complex with sequence-specific DNA-binding and selective methyl-lysine-binding activities. Genes Dev 20: 1110–1122.

    Article  CAS  Google Scholar 

  • Koff A, Giordano A, Desai D, Yamashita K, Harper JW, Elledge S et al. (1992). Formation and activation of a cyclin E-cdk2 complex during the G1 phase of the human cell cycle. Science 257: 1689–1694.

    Article  CAS  Google Scholar 

  • Koga H, Matsui S, Hirota T, Takebayashi S, Okumura K, Saya H . (1999). A human homolog of Drosophila lethal(3)malignant brain tumor (l(3)mbt) protein associates with condensed mitotic chromosomes. Oncogene 18: 3799–3809.

    Article  CAS  Google Scholar 

  • Kohlmaier A, Savarese F, Lachner M, Martens J, Jenuwein T, Wutz A . (2004). A chromosomal memory triggered by Xist regulates histone methylation in X inactivation. PLoS Biol 2: E171.

    Article  Google Scholar 

  • Lachner M, Jenuwein T . (2002). The many faces of histone lysine methylation. Curr Opin Cell Biol 14: 286–298.

    Article  CAS  Google Scholar 

  • Lachner M, O’Carroll D, Rea S, Mechtler K, Jenuwein T . (2001). Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 410: 116–120.

    Article  CAS  Google Scholar 

  • Lewis PW, Beall EL, Fleischer TC, Georlette D, Link AJ, Botchan MR . (2004). Identification of a Drosophila Myb-E2F2/RBF transcriptional repressor complex. Genes Dev 18: 2929–2940.

    Article  CAS  Google Scholar 

  • MacGrogan D, Kalakonda N, Alvarez S, Scandura JM, Boccuni P, Johansson B et al. (2004). Structural integrity and expression of the L3MBTL gene in normal and malignant hematopoietic cells. Genes Chromosomes Cancer 41: 203–213.

    Article  CAS  Google Scholar 

  • Martens JH, O′Sullivan RJ, Braunschweig U, Opravil S, Radolf M, Steinlein P et al. (2005). The profile of repeat-associated histone lysine methylation states in the mouse epigenome. EMBO J 24: 800–812.

    Article  CAS  Google Scholar 

  • Maurer-Stroh S, Dickens NJ, Hughes-Davies L, Kouzarides T, Eisenhaber F, Ponting CP . (2003). The Tudor domain ′Royal Family′: Tudor, plant Agenet, Chromo, PWWP and MBT domains. Trends Biochem Sci 28: 69–74.

    Article  CAS  Google Scholar 

  • Mendez J, Stillman B . (2000). Chromatin association of human origin recognition complex, cdc6, and minichromosome maintenance proteins during the cell cycle: assembly of prereplication complexes in late mitosis. Mol Cell Biol 20: 8602–8612.

    Article  CAS  Google Scholar 

  • Mikkelsen TS, Ku M, Jaffe DB, Issac B, Lieberman E, Giannoukos G et al. (2007). Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448: 553–560.

    Article  CAS  Google Scholar 

  • Nishioka K, Rice JC, Sarma K, Erdjument-Bromage H, Werner J, Wang Y et al. (2002). PR-Set7 is a nucleosome-specific methyltransferase that modifies lysine 20 of histone H4 and is associated with silent chromatin. Mol Cell 9: 1201–1213.

    Article  CAS  Google Scholar 

  • Pesavento JJ, Yang H, Kelleher NL, Mizzen CA . (2008). Certain and progressive methylation of histone H4 at lysine 20 during the cell cycle. Mol Cell Biol 28: 468–486.

    Article  CAS  Google Scholar 

  • Peters AH, Kubicek S, Mechtler K, O′Sullivan RJ, Derijck AA, Perez-Burgos L et al. (2003). Partitioning and plasticity of repressive histone methylation states in mammalian chromatin. Mol Cell 12: 1577–1589.

    Article  CAS  Google Scholar 

  • Pray-Grant MG, Daniel JA, Schieltz D, Yates III JR, Grant PA . (2005). Chd1 chromodomain links histone H3 methylation with SAGA- and SLIK-dependent acetylation. Nature 433: 434–438.

    Article  CAS  Google Scholar 

  • Rice JC, Briggs SD, Ueberheide B, Barber CM, Shabanowitz J, Hunt DF et al. (2003). Histone methyltransferases direct different degrees of methylation to define distinct chromatin domains. Mol Cell 12: 1591–1598.

    Article  CAS  Google Scholar 

  • Rice JC, Nishioka K, Sarma K, Steward R, Reinberg D, Allis CD . (2002). Mitotic-specific methylation of histone H4 Lys 20 follows increased PR-Set7 expression and its localization to mitotic chromosomes. Genes Dev 16: 2225–2230.

    Article  CAS  Google Scholar 

  • Ruthenburg AJ, Allis CD, Wysocka J . (2007). Methylation of lysine 4 on histone H3: intricacy of writing and reading a single epigenetic mark. Mol Cell 25: 15–30.

    Article  CAS  Google Scholar 

  • Schotta G, Ebert A, Krauss V, Fischer A, Hoffmann J, Rea S et al. (2002). Central role of Drosophila SU(VAR)3-9 in histone H3-K9 methylation and heterochromatic gene silencing. EMBO J 21: 1121–1131.

    Article  CAS  Google Scholar 

  • Schotta G, Lachner M, Sarma K, Ebert A, Sengupta R, Reuter G et al. (2004). A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin. Genes Dev 18: 1251–1262.

    Article  CAS  Google Scholar 

  • Seet BT, Dikic I, Zhou MM, Pawson T . (2006). Reading protein modifications with interaction domains. Nat Rev Mol Cell Biol 7: 473–483.

    Article  CAS  Google Scholar 

  • Sims JK, Houston SI, Magazinnik T, Rice JC . (2006). A trans-tail histone code defined by monomethylated H4 Lys-20 and H3 Lys-9 demarcates distinct regions of silent chromatin. J Biol Chem 281: 12760–12766.

    Article  CAS  Google Scholar 

  • Stewart MD, Li J, Wong J . (2005). Relationship between histone H3 lysine 9 methylation, transcription repression, and heterochromatin protein 1 recruitment. Mol Cell Biol 25: 2525–2538.

    Article  CAS  Google Scholar 

  • Talasz H, Lindner HH, Sarg B, Helliger W . (2005). Histone H4-lysine 20 monomethylation is increased in promoter and coding regions of active genes and correlates with hyperacetylation. J Biol Chem 280: 38814–38822.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Trojer P, Li G, Sims III RJ, Vaquero A, Kalakonda N, Boccuni P et al. (2007). L3MBTL1, a histone-methylation-dependent chromatin lock. Cell 129: 915–928.

    Article  CAS  Google Scholar 

  • Turner BM . (2007). Defining an epigenetic code. Nat Cell Biol 9: 2–6.

    Article  CAS  Google Scholar 

  • Vakoc CR, Sachdeva MM, Wang H, Blobel GA . (2006). Profile of histone lysine methylation across transcribed mammalian chromatin. Mol Cell Biol 26: 9185–9195.

    Article  CAS  Google Scholar 

  • Wang WK, Tereshko V, Boccuni P, MacGrogan D, Nimer SD, Patel DJ . (2003). Malignant brain tumor repeats: a three-leaved propeller architecture with ligand/peptide binding pockets. Structure 11: 775–789.

    Article  CAS  Google Scholar 

  • Wismar J, Loffler T, Habtemichael N, Vef O, Geissen M, Zirwes R et al. (1995). The Drosophila melanogaster tumor suppressor gene lethal(3)malignant brain tumor encodes a proline-rich protein with a novel zinc finger. Mech Dev 53: 141–154.

    Article  CAS  Google Scholar 

  • Yohn CB, Pusateri L, Barbosa V, Lehmann R . (2003). l(3)malignant brain tumor and three novel genes are required for Drosophila germ-cell formation. Genetics 165: 1889–1900.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zamir I, Dawson J, Lavinsky RM, Glass CK, Rosenfeld MG, Lazar MA . (1997). Cloning and characterization of a corepressor and potential component of the nuclear hormone receptor repression complex. Proc Natl Acad Sci USA 94: 14400–14405.

    Article  CAS  Google Scholar 

  • Zhang L, Eugeni EE, Parthun MR, Freitas MA . (2003). Identification of novel histone post-translational modifications by peptide mass fingerprinting. Chromosoma 112: 77–86.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We dedicate this paper to the late Piernicola Boccuni, whose beautiful life as a physician–scientist and as a husband, father and friend, ended far too quickly. This work was made possible by grants from the National Institute of Health (SDN), the Leukemia and Lymphoma Society (SDN, XZ), the Herbert and Lee Friedman Fellowship Fund (XZ), the MSKCC Clinical Scholars Program (PB), the Damon Runyon Research Foundation (WF), and the Mel Stottlemyre Research Foundation (NK). We thank Drs C David Allis (The Rockefeller University, NY) for guidance and advice, Wooikoon Wang and Dinshaw Patel (MSKCC, NY) for structural insights; Tarun K Dam and C Fred Brewer (Albert Einstein Medical College, NY) for help with ITC experiments and Andrew Koff (MSKCC, NY) for scientific advice and assistance with centrifugal elutriation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to S D Nimer.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kalakonda, N., Fischle, W., Boccuni, P. et al. Histone H4 lysine 20 monomethylation promotes transcriptional repression by L3MBTL1. Oncogene 27, 4293–4304 (2008). https://doi.org/10.1038/onc.2008.67

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2008.67

Keywords

This article is cited by

Search

Quick links