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:

Functional long-range interactions of the IgH 3′ enhancers with the bcl-2 promoter region in t(14;18) lymphoma cells

Oncogene volume 27, pages 6720–6728 (2008)Cite this article

Abstract

To better understand the mechanisms underlying the role of the immunoglobulin heavy-chain gene (IgH) 3′ enhancers on bcl-2 transcriptional deregulation in t(14;18) lymphoma, we characterized the physical interactions of the IgH 3′ enhancer region with the bcl-2 promoters. Using the chromosome conformation capture technique, we found that the IgH 3′ enhancers physically interact with the bcl-2 promoter region over a 350 kb genomic region in t(14;18) lymphoma cells. No interactions of the bcl-2 promoter region with sequences distant to the IgH enhancers were observed. The physical interactions of the IgH enhancers with the bcl-2 5′ region are functionally involved in the transcriptional control of bcl-2. The histone deacetylase inhibitor, trichostatin A, repressed bcl-2 transcription and decreased the IgH enhancer-bcl-2 promoter region interactions. We showed by chromatin immunoprecipitation assay and small interference RNA transfection studies that the POU2 family transcription factor Oct-2 and its cofactor Bob-1 have an important function in mediating the IgH enhancer-bcl-2 promoter region interactions. This study reveals a new aspect of the regulatory role of the IgH 3′ enhancers on bcl-2 transcription in t(14;18) lymphomas.

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
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Dekker J, Rippe K, Dekker M, Kleckner N . (2002). Capturing chromosome conformation. Science 295: 1306–1311.

    Article  CAS  Google Scholar 

  • Desoize B . (1994). Anticancer drug resistance and inhibition of apoptosis. Anticancer Res 14: 2291–2294.

    CAS  PubMed  Google Scholar 

  • Duan H, Heckman CA, Boxer LM . (2005). Histone deacetylase inhibitors down-regulate bcl-2 expression and induce apoptosis in t(14;18) lymphomas. Mol Cell Biol 25: 1608–1619.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duan H, Heckman CA, Boxer LM . (2007). The immunoglobulin heavy-chain gene 3′ enhancers deregulate bcl-2 promoter usage in t(14;18) lymphoma cells. Oncogene 26: 2635–2641.

    Article  CAS  PubMed  Google Scholar 

  • Graninger WB, Seto M, Boutain B, Goldman P, Korsmeyer SJ . (1987). Expression of bcl-2 and bcl-2-Ig fusion transcripts in normal and neoplastic cells. J Clin Invest 80: 1512–1515.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hagege H, Klous P, Braem C, Splinter E, Dekker J, Cathala G et al. (2007). Quantitative analysis of chromosome conformation capture assays (3C-qPCR). Nature Protocols 2: 1722–1733.

    Article  CAS  PubMed  Google Scholar 

  • Heckman CA, Cao T, Somsouk L, Duan H, Mehew JW, Zhang C et al. (2003a). Critical elements of the immunoglobulin heavy chain gene enhancers for deregulated expression of bcl-2. Cancer Res 63: 6666–6673.

    CAS  PubMed  Google Scholar 

  • Heckman CA, Duan H, Garcia PB, Boxer LM . (2006). Oct transcription factors mediate t(14;18) lymphoma cell survival by directly regulating bcl-2 expression. Oncogene 25: 888–898.

    Article  CAS  PubMed  Google Scholar 

  • Heckman CA, Mehew JW, Boxer LM . (2002). NF-êB activates bcl-2 expression in t(14;18) lymphoma cells. Oncogene 21: 3898–3908.

    Article  CAS  PubMed  Google Scholar 

  • Heckman CA, Mehew JW, Ying G-G, Introna M, Golay J, Boxer LM . (2000). A-Myb up-regulates Bcl-2 through a Cdx binding site in t(14;18) lymphoma cells. J Biol Chem 275: 6499–6508.

    Article  CAS  Google Scholar 

  • Heckman CA, Wheeler MA, Boxer LM . (2003b). Regulation of Bcl-2 expression by C/EBP in t(14;18) lymphoma cells. Oncogene 22: 7891–7899.

    Article  PubMed  Google Scholar 

  • Hockenberry D, Nunez G, Milliman C, Schreiber RD, Korsmeyer SJ . (1990). Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 348: 334–336.

    Article  Google Scholar 

  • Ji L, Mochon E, Arcinas M, Boxer LM . (1996). CREB proteins function as positive regulators of the translocated bcl-2 allele in t(14;18) lymphomas. J Biol Chem 271: 22687–22691.

    Article  CAS  PubMed  Google Scholar 

  • Ju Z, Volpi SA, Hassan R, Martinez N, Giannini SL, Gold T et al. (2007). Evidence for physical interaction between the immunoglobulin heavy chain variable region and the 3′ regulatory region. J Biol Chem 282: 35169–35178.

    Article  CAS  PubMed  Google Scholar 

  • Khamlichi AA, Pinaud E, Decourt C, Chauveau C, Cogne M . (2000). The 3′ IgH regulatory region: a complex structure in a search for a function. Adv Immunol 75: 317–345.

    Article  CAS  PubMed  Google Scholar 

  • Liu Z, Garrard WT . (2005). Long-range interactions between three transcriptional enhancers, active Vκ gene promoters, and a 3′ boundary sequence spanning 46 kilobases. Mol Cell Biol 25: 3220–3231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Madisen L, Groudine M . (1994). Identification of a locus control region in the immunoglobulin heavy-chain locus that deregulates c-myc expression in plasmacytoma and Burkitt's lymphoma cells. Gene Devel 8: 2212–2226.

    Article  CAS  Google Scholar 

  • Miele A, Gheldof N, Tabuchi TM, Dostie J, Dekker J . (2006). Mapping chromatin interactions by chromosome conformation capture (3C). In: Ausubel FM, Brent R, Kingston RE, Moore DD, Seidman JG, Smith JA et al. (eds). Current Protocols in Molecular Biology. John Wiley & Sons: New York, pp 21.11.1–21.11.20.

    Google Scholar 

  • Mills FC, Harindranath N, Mitchell M, Max EE . (1997). Enhancer complexes located downstream of both human immunoglobulin C-alpha genes. J Exp Med 186: 845–858.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Palstra R-J, Tolhuis B, Splinter E, Nijmeijer R, Grosveld F, de Laat W . (2003). The β-globlin nuclear compartment in development and erythroid differentiation. Nat Genet 35: 190–194.

    Article  CAS  PubMed  Google Scholar 

  • Reed JC, Kitada S, Takayama S, Miyashita T . (1994). Regulation of chemoresistance by the bcl-2 oncoprotein in non-Hodgkin's lymphoma and lymphocytic leukemia cell lines. Ann Oncol 5 (Suppl 1): S61–S65.

    Article  Google Scholar 

  • Schmitt CA, Lowe SW . (2001). Bcl-2 mediates chemoresistance in matched pairs of primary Eμ-myc lymphomas in vivo. Blood Cells Mol Dis 27: 206–216.

    Article  CAS  PubMed  Google Scholar 

  • Seto M, Jaeger U, Hockett RD, Graninger W, Bennett S, Goldman P et al. (1988). Alternative promoters and exons, somatic mutation and deregulation of the Bcl-2-Ig fusion gene in lymphoma. EMBO J 7: 123–131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Splinter E, Grosveld F, de Laat W . (2004). 3C technology: analyzing the spatial organization of genomic loci in vivo. Methods Enzymol 375: 493–507.

    Article  CAS  PubMed  Google Scholar 

  • Tolhuis B, Palstra R-J, Splinter E, Grosveld F, de Laat W . (2002). Looping and interaction between hypersensitive sites in the active β-globin locus. Mol Cell 10: 1453–1465.

    Article  CAS  Google Scholar 

  • Wilson BE, Mochon E, Boxer LM . (1996). Induction of bcl-2 expression by phosphorylated CREB proteins during B-cell activation and rescue from apoptosis. Mol Cell Biol 16: 5546–5556.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by National Institutes of Health Grant CA56764. We are grateful to Dr Job Dekker (U Mass) for advice and for providing the 3C protocol, and to Drs Tao Li, Jianqun Lin and Xinwen Qiu in Dr Andrew Hoffman's laboratory at Stanford University for expert assistance with the 3C analysis.

Author information

Authors and Affiliations

  1. Center for Molecular Biology in Medicine, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA

    H Duan, H Xiang, L Ma & L M Boxer

  2. Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA

    H Duan, H Xiang, L Ma & L M Boxer

Authors
  1. H Duan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H Xiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L M Boxer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L M Boxer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Duan, H., Xiang, H., Ma, L. et al. Functional long-range interactions of the IgH 3′ enhancers with the bcl-2 promoter region in t(14;18) lymphoma cells. Oncogene 27, 6720–6728 (2008). https://doi.org/10.1038/onc.2008.286

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2008.286

Keywords

This article is cited by

Search

Advanced search

Quick links