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:

The H3K27me3 demethylase, KDM6B, is induced by Epstein–Barr virus and over-expressed in Hodgkin's Lymphoma

Abstract

There is now evidence for both increased and decreased activity of the enzymes controlling the methylation of lysine 27 on histone 3 (H3K27) in cancer. One of these enzymes, KDM6B formally known as JMJD3, a histone demethylase, which removes the trimethyl mark from H3K27, is required for the lineage commitment and terminal differentiation of neural stem cells and of keratinocytes. Our results suggest that KDM6B may also have a role in antigen-driven B-cell differentiation. KDM6B expression increases in B-cell subsets with increasing stage of differentiation, and gene expression profiling shows that KDM6B transcriptional targets in germinal centre B (GC B) cells are significantly enriched for those differentially expressed during memory and plasma cell differentiation. Our results also suggest that aberrant expression of KDM6B may contribute to the pathogenesis of Hodgkin's Lymphoma (HL), an Epstein–Barr virus (EBV) associated malignancy. KDM6B is over-expressed in primary HL and induced by the EBV oncogene, latent membrane protein (LMP1) in GC B cells, the presumptive progenitors of HL. Consistent with these observations, we found that KDM6B transcriptional targets in GC B cells are enriched for genes differentially expressed in HL, and that KDM6B depletion can restore the tri-methylation of H3K27 on these genes.

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

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  • Agger K, Cloos PA, Rudkjær L, Williams K, Andersen G, Christensen J et al. (2009). The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A – ARF locus in response to oncogene- and stress-induced senescence. Genes Dev 23: 1171–1176.

    Article  CAS  Google Scholar 

  • Agger K, Cloos Pa, Christensen J, Pasini D, Rose S, Rappsilber J et al. (2007). UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development. Nature 449: 731–734.

    Article  CAS  Google Scholar 

  • Agherbi H, Gaussmann-Wenger A, Verthuy C, Chasson L, Serrano M, Djabali M et al. (2009). Polycomb mediated epigenetic silencing and replication timing at the INK4a/ARF locus during senescence. PloS one 4: e5622. doi: 10.1371/journal.pone.0005622.

    Article  CAS  Google Scholar 

  • Aldinucci D, Gloghini A, Pinto A, De Filippi R, Carbone A . (2010). The classical Hodgkin's lymphoma microenvironment and its role in promoting tumour growth and immune escape. J Pathol 221: 248–263.

    Article  CAS  Google Scholar 

  • Barradas M, Anderton E, Acosta JC, Li S, Banito A, Rodriguez-Niedenführ M et al. (2009). Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS. Genes Dev 23: 1177–1182.

    Article  CAS  Google Scholar 

  • Brune V, Tiacci E, Pfeil I, Döring C, Eckerle S, van Noesel CJ et al. (2008). Origin and pathogenesis of nodular lymphocyte-predominant Hodgkin lymphoma as revealed by global gene expression analysis. J Exp Med 205: 2251–2268.

    Article  CAS  Google Scholar 

  • Burgold T, Spreafico F, De Santa F, Totaro MG, Prosperini E, Natoli G et al. (2008). The histone H3 lysine 27-specific demethylase Jmjd3 is required for neural commitment. PloS one 3: e3034. doi: 10.1371/journal.pone.0003034.

    Article  CAS  Google Scholar 

  • Dai J, Lu J, Zhang Y, Shen Y . (2010). Jmjd3 activates Mash1 gene in RA-induced neuronal differentiation of P19 cells. J Cell Biochem 110: 1457–1463.

    Article  CAS  Google Scholar 

  • De Santa F, Narang V, Yap ZH, Tusi BK, Burgold T, Austenaa L et al. (2009). Jmjd3 contributes to the control of gene expression in LPS-activated macrophages. EMBO J 28: 3341–3352.

    Article  CAS  Google Scholar 

  • De Santa F, Totaro MG, Prosperini E, Notarbartolo S, Testa G, Natoli G et al. (2007). The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing. Cell 130: 1083–1094.

    Article  CAS  Google Scholar 

  • Delecluse HJ, Hilsendegen T, Pich D, Zeidler R, Hammerschmidt W . (1998). Propagation and recovery of intact, infectious Epstein-Barr virus from prokaryotic to human cells. Proc Natl Acad Sci USA 95: 8245–8250.

    Article  CAS  Google Scholar 

  • Dirmeier U, Hoffmann R, Kilger E, Schultheiss U, Briseño C, Gires O et al. (2005). Latent membrane protein 1 of Epstein-Barr virus coordinately regulates proliferation with control of apoptosis. Oncogene 24: 1711–1717.

    Article  CAS  Google Scholar 

  • Fei T, Xia K, Li Z, Zhou B, Zhu S, Chen H et al. (2010). Genome-wide mapping of SMAD target genes reveals the role of BMP signaling in embryonic stem cell fate determination. Genome Res 20: 36–44.

    Article  CAS  Google Scholar 

  • Günther T, Grundhoff A . (2010). The epigenetic landscape of latent kaposi sarcoma-associated herpesvirus genomes. PLoS Pathogens 6: e1000935.

    Article  Google Scholar 

  • Haaften GV, Dalgliesh GL, Davies H, Chen L, Greenman C, Edkins S et al. (2010). UKPMC. Funders Group Human Cancer 41: 521–523.

    Google Scholar 

  • Hellerbrand C, Jobin C, Iimuro Y, Licato L, Sartor RB, Brenner DA . (1998). Inhibition of NFkappaB in activated rat hepatic stellate cells by proteasome inhibitors and an IkappaB super-repressor. Hepatology 27: 1285–1295.

    Article  CAS  Google Scholar 

  • Holland D, Hoppe-Seyler K, Schuller B, Lohrey C, Maroldt J, Dürst M et al. (2008). Activation of the enhancer of zeste homologue 2 gene by the human papillomavirus E7 oncoprotein. Cancer Res 68: 9964–9972.

    Article  CAS  Google Scholar 

  • Hong S, Cho Y, Yu L, Yu H, Veenstra TD, Ge K et al. (2007). Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases. Proc Natl Acad Sci USA 104: 18439–18444.

    Article  CAS  Google Scholar 

  • Ishii M, Wen H, Corsa CA, Liu T, Coelho AL, Allen RM et al. (2009). Epigenetic regulation of the alternatively activated macrophage phenotype. Blood 114: 3244–3254.

    Article  CAS  Google Scholar 

  • Jepsen K, Solum D, Zhou T, McEvilly RJ, Kim H, Glass CK et al. (2007). SMRT-mediated repression of an H3K27 demethylase in progression from neural stem cell to neuron. Nature 450: 415–419.

    Article  CAS  Google Scholar 

  • Ledebur HC, Parks TP . (1995). Transcriptional regulation of the intercellular adhesion molecule-1 gene by inflammatory cytokines in human endothelial cells. Essential roles of a variant NF-kB site and p65 homodimers. J Biol Chem 270: 933–943.

    Article  CAS  Google Scholar 

  • Mainou-Fowler T . (2004). Interleukin 4 production by peripheral blood lymphocytes in patients with classical Hodgkin lymphoma. Leukemia Res 28: 159–166.

    Article  CAS  Google Scholar 

  • Morin RD, Johnson Na, Severson TM, Mungall AJ, An J, Goya R et al. (2010). Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet 42: 181–185.

    Article  CAS  Google Scholar 

  • Neuhierl B, Feederle R, Hammerschmidt W, Delecluse HJ . (2002). Glycoprotein gp110 of Epstein-Barr virus determines viral tropism and efficiency of infection. Proc Natl Acad Sci USA 99: 15036–15041.

    Article  CAS  Google Scholar 

  • Raaphorst FM, Kemenade FJ, Blokzijl T, Fieret E, Hamer KM, Satijn DP et al. (2000). Genes in reed-sternberg cells of Hodgkin's disease. Am J Pathol 157: 40–42.

    Article  Google Scholar 

  • Sandvej KB, Hamilton-Dutoit SJ, Pallensen G . (1993). Influence of Epstein-Barr virus encoded latent membrane protein on the expression of CD23 antigen, ICAM-1 and LFA-3 in Hodgkin and Reed-Sternberg cells. A morphometric analysis. Leuk Lymphoma 9: 95–101.

    Article  CAS  Google Scholar 

  • Sen GL, Webster DE, Barragan DI, Chang HY, Khavari PA . (2008). Control of differentiation in a self-renewing mammalian tissue by the histone demethylase JMJD3. Genes Dev 22: 1865–1870.

    Article  CAS  Google Scholar 

  • Shannon-Lowe C, Baldwin G, Feederle R, Bell A, Rickinson A, Delecluse H et al. (2005). Epstein-Barr virus-induced B-cell transformation: quantitating events from virus binding to cell outgrowth. J Gen Virol 86: 3009–3019.

    Article  CAS  Google Scholar 

  • Simon JA, Lange CA . (2008). Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mutat Res 647: 21–29.

    Article  CAS  Google Scholar 

  • Skinnider BF, Elia AJ, Gascoyne RD, Patterson B, Trumper L, Kapp U et al. (2002). Signal transducer and activator of transcription 6 is frequently activated in Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma. Blood 99: 618–626.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Vockerodt M, Morgan SL, Kuo M, Wei W, Chukwuma MB, Arrand JR et al. (2008). The Epstein–Barr virus oncoprotein, latent membrane protein-1, reprograms germinal centre B cells towards a Hodgkin's Reed–Sternberg-like phenotype. J Pathol 216: 83–92.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Leukaemia and Lymphoma Research Fund.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to C B Woodman.

Ethics declarations

Competing interests

These authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Anderton, J., Bose, S., Vockerodt, M. et al. The H3K27me3 demethylase, KDM6B, is induced by Epstein–Barr virus and over-expressed in Hodgkin's Lymphoma. Oncogene 30, 2037–2043 (2011). https://doi.org/10.1038/onc.2010.579

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2010.579

Keywords

This article is cited by

Search

Quick links