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.

  • Review Article
  • Published:

Gene segment selection in V(D)J recombination: accessibility and beyond

Nature Immunology volume 4, pages 624–630 (2003)Cite this article

Abstract

V(D)J recombination assembles genes encoding antigen receptors according to defined developmental programs in immature B and T lymphocytes. The 'accessibility hypothesis' was initially invoked to explain how a single recombinase complex could control the locus and allele specificity of V(D)J recombination. It has been since shown that recombination signal sequences themselves influence recombination efficiency and specificity in ways that had not been previously appreciated. Recent developments have increased our understanding of how the chromatin barrier to V(D)J recombination is regulated, and how chromatin control and the properties of the underlying recombination signal sequences may cooperate to create diverse, lineage-restricted and allelically excluded repertoires of antigen receptors.

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: The V(D)J recombination reaction.
Figure 2: Stages of Ig and TCR gene V(D)J recombination events during the development of B and T lymphocytes.
Figure 3: Regional control of the Tcrb and Tcra/Tcrd loci by enhancers and promoters.
Figure 4: The beyond 12/23 restriction imposed by RSSs regulates Vβ to DJβ rearrangement.

Similar content being viewed by others

References

  1. Fugmann, S.D., Lee, A.I., Shockett, P.E., Villey, I.J. & Schatz, D.G. The RAG proteins and V(D)J recombination: complexes, ends and transposition. Annu. Rev. Immunol. 18, 495–527 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Bassing, C.H., Swat, W. & Alt, F.W. The mechanism and regulation of chromosomal V(D)J recombination. Cell 109, S45–S55 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. Hesslein, D.G.T. & Schatz, D.G. Factors and forces controlling V(D)J recombination. Adv. Immunol. 78, 169–232 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Yancopoulos, G. & Alt, F. Developmentally controlled and tissue-specific expression of unrearranged VH gene segments. Cell 40, 271–281 (1985).

    Article  CAS  PubMed  Google Scholar 

  5. Stanhope-Baker, P., Hudson, K.M., Shaffer, A.L., Constantinescu, A. & Schlissel, M.S. Cell type-specific chromatin structure determines the targeting of V(D)J recombinase activity in vitro. Cell 85, 887–897 (1996).

    Article  CAS  PubMed  Google Scholar 

  6. Kwon, J., Imbalzano, A.N., Matthews, A. & Oettinger, M.A. Accessibility of nucleosomal DNA to V(D)J cleavage is modulated by RSS positioning and HMG1. Mol. Cell 2, 829–839 (1998).

    Article  CAS  PubMed  Google Scholar 

  7. Golding, A., Chandler, S., Ballestar, E., Wolffe, A.P. & Schlissel, M.S. Nucleosome structure completely inhibits in vitro cleavage by the V(D)J recombinase. EMBO J. 18, 3712–3723 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bories, J.-C., Demengeot, J., Davidson, L. & Alt, F.W. Gene-targeted deletion and replacement of the T-cell receptor β-chain enhancer: The role of enhancer elements in controlling V(D)J recombination accessibility. Proc. Natl. Acad. Sci. USA 93, 7871–7876 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bouvier, G. et al. Deletion of the mouse T-cell receptor β gene enhancer blocks αβ T-cell development. Proc. Natl. Acad. Sci. USA 93, 7877–7881 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sleckman, B.P., Bardon, C.G., Ferrini, R., Davidson, L. & Alt, F.W. Function of the TCRα enhancer in αβ and γδ T cells. Immunity 7, 505–515 (1997).

    Article  CAS  PubMed  Google Scholar 

  11. Inlay, M., Alt, F.W., Baltimore, D. & Xu, Y. Essential roles of the κ light chain intronic enhancer and 3′ enhancer in κ rearrangement and demethylation. Nat. Immunol. 3, 463–468 (2002).

    Article  CAS  PubMed  Google Scholar 

  12. Capone, M. et al. TCRβ and TCRα gene enhancers confer tissue- and stage-specificity on V(D)J recombination events. EMBO J. 12, 4335–4346 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lauzurica, P. & Krangel, M.S. Temporal and lineage-specific control of T cell receptor α/δ gene rearrangement by T cell receptor α and δ enhancers. J. Exp. Med. 179, 1913–1921 (1994).

    Article  CAS  PubMed  Google Scholar 

  14. Hernandez-Munain, C., Sleckman, B.P. & Krangel, M.S. A developmental switch from TCRδ enhancer to TCRα enhancer function during thymocyte maturation. Immunity 10, 723–733 (1999).

    Article  CAS  PubMed  Google Scholar 

  15. Villey, I., Caillol, D., Selz, F., Ferrier, P. & de Villartay, J.-P. Defect in rearrangement of the most 5′ TCR-Jα following targeted deletion of T early α (TEA): implications for TCR α locus accessibility. Immunity 5, 331–342 (1996).

    Article  CAS  PubMed  Google Scholar 

  16. Sikes, M.L., Suarez, C.C. & Oltz, E.M. Regulation of V(D)J recombination by transcriptional promoters. Mol. Cell. Biol. 19, 2773–2781 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Whitehurst, C.E., Chattopadhyay, S. & Chen, J. Control of V(D)J recombinational accessibility of the Dβ1 gene segment at the TCRβ locus by a germline promoter. Immunity 10, 313–322 (1999).

    Article  CAS  PubMed  Google Scholar 

  18. McMurry, M.T., Hernandez-Munain, C., Lauzurica, P. & Krangel, M.S. Enhancer control of local accessibility to V(D)J recombinase. Mol. Cell. Biol. 17, 4553–4561 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hempel, W.M. et al. Enhancer control of V(D)J recombination at the TCRβ locus: differential effects on DNA cleavage and joining. Genes Dev. 12, 2305–2317 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Whitehurst, C.E., Schlissel, M.S. & Chen, J. Deletion of germline promoter PDβ1 from the TCRβ locus causes hypermethylation that impairs Dβ1 recombination by multiple mechanisms. Immunity 13, 703–714 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Fernex, C., Capone, M. & Ferrier, P. The V(D)J recombinational and transcriptional activities of the immunoglobulin heavy-chain intronic enhancer can be mediated through distinct protein-binding sites in a transgenic substrate. Mol. Cell. Biol. 15, 3217–3226 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Tripathi, R.K. et al. Definition of a T-cell receptor β gene core enhancer of V(D)J recombination by transgenic mapping. Mol. Cell. Biol. 20, 42–53 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Angelin-Duclos, C. & Calame, K. Evidence that immunoglobulin VH-DJ recombination does not require germ line transcription of the recombining variable gene segment. Mol. Cell. Biol. 18, 6253–6264 (1999).

    Article  Google Scholar 

  24. Sikes, M.L., Meade, A., Tripathi, R., Krangel, M.S. & Oltz, E.M. Regulation of V(D)J recombination: A dominant role for promoter positioning in gene segment accessibility. Proc. Natl. Acad. Sci. USA 99, 12309–12314 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. McMurry, M.T. & Krangel, M.S. A role for histone acetylation in the developmental regulation of V(D)J recombination. Science 287, 495–498 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Mathieu, N., Hempel, W.M., Spicuglia, S., Verthuy, C. & Ferrier, P. Chromatin remodeling by the T cell receptor (TCR)-β gene enhancer during early T cell development: implications for the control of TCR-β locus recombination. J. Exp. Med. 192, 625–636 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Agata, Y. et al. Histone acetylation determines the developmentally regulated accessibility for T cell receptor-γ gene recombination. J. Exp. Med. 193, 873–879 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Huang, J., Durum, S.K. & Muegge, K. Cutting edge: histone acetylation and recombination at the TCR γ locus follows IL-7 induction. J. Immunol. 167, 6073–6077 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. McBlane, F. & Boyes, J. Stimulation of V(D)J recombination by histone acetylation. Curr. Biol. 10, 483–486 (2000).

    Article  CAS  PubMed  Google Scholar 

  30. Cherry, S.R. & Baltimore, D. Chromatin remodeling directly activates V(D)J recombination. Proc. Natl. Acad. Sci. USA 96, 10788–10793 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kwon, J., Morshead, K.B., Guyon, J.R., Kingston, R.E. & Oettinger, M.A. Histone acetylation and hSWI/SNF remodeling act in concert to stimulate V(D)J cleavage of nucleosomal DNA. Mol. Cell 6, 1037–1048 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Tse, C., Sera, T., Wolffe, A.P. & Hansen, J.C. Disruption of higher-order folding by core histone acetylation dramatically enhances transcription of nucleosomal arrays by RNA polymerase III. Mol. Cell. Biol. 18, 4629–4638 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Narlikar, G.J., Fan, H.Y. & Kingston, R.E. Cooperation between complexes that regulate chromatin structure and transcription. Cell 108, 475–487 (2002).

    Article  CAS  PubMed  Google Scholar 

  34. Strahl, B.D. & Allis, D. The language of covalent histone modifications. Nature 403, 41–45 (2000).

    Article  CAS  PubMed  Google Scholar 

  35. Jenuwein, T. & Allis, C.D. Translating the histone code. Science 293, 1074–1080 (2001).

    Article  CAS  PubMed  Google Scholar 

  36. Spicuglia, S. et al. Promoter activation by enhancer-dependent and -independent loading of activator and coactivator complexes. Mol. Cell 10, 1479–1487 (2002).

    Article  CAS  PubMed  Google Scholar 

  37. Su, I.H. et al. Ezh2 controls B cell development through histone H3 methylation and Igh rearrangement. Nat. Immunol. 4, 124–131 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Ng, H.H., Ciccone, D.N., Morshead, K.B., Oettinger, M.A. & Struhl, K. Lysine-79 of histone H3 is hypomethylated at silenced loci in yeast and mammalian cells: a potential mechanism for position-effect variegation. Proc. Natl. Acad. Sci. USA 100, 1820–1825 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Hsieh, C.-L. & Lieber, M.R. CpG methylated minichromosomes become inaccessible for V(D)J recombination after undergoing replication. EMBO J. 11, 315–325 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Mostoslavsky, R. et al. κ chain monoallelic demethylation and the establishment of allelic exclusion. Genes Dev. 12, 1801–1811 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Cherry, S.R., Beard, C., Jaenisch, R. & Baltimore, D. V(D)J recombination is not activated by demethylation of the κ locus. Proc. Natl. Acad. Sci. USA 97, 8467–8472 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Villey, I., Quartier, P., Selz, F. & de Villartay, J.-P. Germ-line transcription and methylation status of the TCR-Jα locus in its accessible configuration. Eur. J. Immunol. 27, 1619–1625 (1997).

    Article  CAS  PubMed  Google Scholar 

  43. Senoo, M. & Shinkai, Y. Regulation of Vβ germline transcription in RAG-deficient mice by the CD3ε-mediated signals: implications of Vβ transcriptional regulation in TCR β allelic exclusion. Int. Immunol. 10, 553–560 (1998).

    Article  CAS  PubMed  Google Scholar 

  44. Yannoutsos, N. et al. The role of recombination activating gene (RAG) reinduction in thymocyte development in vivo. J. Exp. Med. 194, 471–480 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Guo, J. et al. Regulation of the TCRα repertoire by the survival window of CD4+CD8+ thymocytes. Nat. Immunol. 3, 469–476 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Mauvieux, L., Villey, I. & de Villartay, J.-P. T early α (TEA) regulates initial TCRVAJA rearrangements and leads to TCRJA coincidence. Eur. J. Immunol. 31, 2080–2086 (2001).

    Article  CAS  PubMed  Google Scholar 

  47. Agalioti, T. et al. Ordered recruitment of chromatin modifying and general transcription factors to the IFN-β promoter. Cell 103, 667–678 (2000).

    Article  CAS  PubMed  Google Scholar 

  48. Kuo, M.-H., vom Baur, E., Struhl, K. & Allis, C.D. Gcn4 activator targets Gcn5 histone acetyltransferase to specific promoters independently of transcription. Mol. Cell 6, 1309–1320 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Vignali, M., Steger, D.J., Neely, K.E. & Workman, J.L. Distribution of acetylated histones resulting from Gal4-VP16 recruitment of SAGA and NuA4 complexes. EMBO J. 19, 2629–2640 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Travers, A. Chromatin modification by DNA tracking. Proc. Natl. Acad. Sci. USA 96, 13634–13637 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Orphanides, G. & Reinberg, D. RNA polymerase II elongation through chromatin. Nature 407, 471–475 (2000).

    Article  CAS  PubMed  Google Scholar 

  52. Feeney, A.J., Tang, A. & Ogwaro, K.M. B-cell repertoire formation: role of the recombination signal sequence in non-random V segment utilization. Immunol. Rev. 175, 59–69 (2000).

    Article  CAS  PubMed  Google Scholar 

  53. Cowell, L.G., Davila, M., Yang, K., Kepler, T.B. & Kelsoe, G. Prospective estimation of recombination signal efficiency and identification of functional cryptic signals in the genome by statistical modeling. J. Exp. Med. 197, 207–220 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Livak, F., Burtrum, D.B., Rowen, L., Schatz, D.G. & Petrie, H.T. Genetic modulation of T cell receptor gene segment usage during somatic recombination. J. Exp. Med. 192, 1191–1196 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Yu, K., Taghva, A. & Lieber, M.R. The cleavage efficiency of the human immunoglobulin heavy chain VH elements by the RAG complex: implications for the immune repertoire. J. Biol. Chem. 277, 5040–5046 (2002).

    Article  CAS  PubMed  Google Scholar 

  56. Bassing, C.H. et al. Recombination signal sequences restrict chromosomal V(D)J recombination beyond the 12/23 rule. Nature 405, 583–586 (2000).

    Article  CAS  PubMed  Google Scholar 

  57. Sleckman, B.P. et al. Mechanisms that direct ordered assembly of T cell receptor β locus V, D, and J gene segments. Proc. Natl. Acad. Sci. USA 97, 7975–7980 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Jung, D., Bassing, C.H., Cheng, H.-L., Schatz, D.G. & Alt, F.W. Extrachromosomal recombination substrates recapitulate beyond 12/23 restricted V(D)J recombination in nonlymphoid cells. Immunity 18, 65–74 (2003).

    Article  CAS  PubMed  Google Scholar 

  59. Tillman, R.E. et al. Cutting Edge: Targeting of Vβ to Dβ rearrangement by RSSs can be mediated by the V(D)J recombinase in the absence of additional lymphoid-specific factors. J. Immunol. 170, 5–9 (2003).

    Article  CAS  PubMed  Google Scholar 

  60. Liang, H.E. et al. The “dispensable” portion of RAG2 is necessary for efficient V-to-DJ rearrangement during B and T cell development. Immunity 17, 639–651 (2002).

    Article  CAS  PubMed  Google Scholar 

  61. Wu, C. et al. Dramatically increased rearrangement and peripheral representation of Vβ14 driven by the 3′ Dβ1 recombination signal sequence. Immunity 18, 75–85 (2003).

    Article  CAS  PubMed  Google Scholar 

  62. Gauss, G.H. & Lieber, M.R. The basis for the mechanistic bias for deletional over inversional V(D)J recombination. Genes Dev. 6, 1553–1561 (1992).

    Article  CAS  PubMed  Google Scholar 

  63. VanDyk, L.F., Wise, T.W., Moore, B.B. & Meek, K. Immunoglobulin DH recombination signal sequence targeting: effect of DH coding and flanking regions and recombination partner. J. Immunol. 157, 4005–4015 (1996).

    CAS  PubMed  Google Scholar 

  64. Pan, P.Y., Lieber, M.R. & Teale, J.M. The role of recombination signal sequences in the preferential joining by deletion in DH-JH recombination and in the ordered rearrangement of the IgH locus. Int. Immunol. 9, 515–522 (1997).

    Article  CAS  PubMed  Google Scholar 

  65. Jones, J.M. & Gellert, M. Ordered assembly of the V(D)J synaptic complex ensures accurate recombination. EMBO J. 21, 4162–4171 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Mundy, C.L., Patenge, N., Matthews, A.G. & Oettinger, M.A. Assembly of the RAG1/RAG2 synaptic complex. Mol. Cell. Biol. 22, 69–77 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Chowdhury, D. & Sen, R. Stepwise activation of the immunoglobulin μ heavy chain gene locus. EMBO J. 20, 6394–6403 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Forsberg, E.C. & Bresnick, E.H. Histone acetylation beyond promoters: long-range acetylation patterns in the chromatin world. BioEssays 23, 820–830 (2001).

    Article  CAS  PubMed  Google Scholar 

  69. Bulger, M., Sawado, T., Schubeler, D. & Groudine, M. ChIPs of the β-globin locus: unraveling gene regulation within an active domain. Curr. Opin. Genet. Dev. 12, 170–177 (2002).

    Article  CAS  PubMed  Google Scholar 

  70. Schubeler, D. et al. Nuclear localization and histone acetylation: a pathway for chromatin opening and transcriptional activation of the human β-globin locus. Genes Dev. 14, 940–950 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Gribnau, J., Diderich, K., Pruzina, S., Calzolari, R. & Fraser, P. Intergenic transcription and developmental remodeling of chromatin subdomains in the human β-globin locus. Mol. Cell 5, 377–386 (2000).

    Article  CAS  PubMed  Google Scholar 

  72. Smale, S.T. Core promoters: active contributors to combinatorial gene regulation. Genes Dev. 15, 2503–2508 (2001).

    Article  CAS  PubMed  Google Scholar 

  73. West, A.G., Gaszner, M. & Felsenfeld, G. Insulators: many functions, many mechanisms. Genes Dev. 16, 271–288 (2002).

    Article  PubMed  CAS  Google Scholar 

  74. Zhong, X.-P. & Krangel, M.S. An enhancer-blocking element between α and δ gene segments within the human T cell receptor α/δ locus. Proc. Natl. Acad. Sci. USA 94, 5219–5224 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Sleckman, B.P., Carabana, J., Zhong, X.-P. & Krangel, M.S. Assessing a role for enhancer-blocking activity in gene regulation within the murine T-cell receptor α/δ locus. Immunology 102 (2001).

  76. Melchers, F., ten Boekel, E., Yamagami, T., Andersson, J. & Rolink, A. The roles of preB and B cell receptors in the stepwise allelic exclusion of mouse IgH and L chain gene loci. Semin. Immunol. 11, 307–317 (1999).

    Article  CAS  PubMed  Google Scholar 

  77. Khor, B. & Sleckman, B.P. Allelic exclusion at the TCRβ locus. Curr. Opin. Immunol. 14, 230–234 (2002).

    Article  CAS  PubMed  Google Scholar 

  78. Chang, Y., Bosma, M.J. & Bosma, G.C. Extended duration of DH-JH rearrangement in immunoglobulin heavy chain transgenic mice: implications for regulation of allelic exclusion. J. Exp. Med. 189, 1295–1305 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Tripathi, R., Jackson, A. & Krangel, M.S. A change in the structure of Vβ chromatin associated with TCRβ allelic exclusion. J. Immunol. 168, 2316–2324 (2002).

    Article  CAS  PubMed  Google Scholar 

  80. Chowdhury, D. & Sen, R. Transient IL-7/IL-7R signaling provides a mechanism for feedback inhibition of immunoglobulin heavy chain gene rearrangements. Immunity 18, 229–241 (2003).

    Article  CAS  PubMed  Google Scholar 

  81. Johnson, K., Angelin-Duclos, C., Park, S. & Calame, K.L. Changes in histone acetylation are associated with differences in accessibility of VH gene segments to V-DJ recombination during B-cell ontogeny and development. Mol. Cell. Biol. 23, 2438–2450 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Lauster, R. et al. Promoter, enhancer and silencer elements regulate rearrangement of an immunoglobulin transgene. EMBO J. 12, 4615–4623 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Baker, J.E., Cado, D. & Raulet, D.H. Developmentally programmed rearrangement of T cell receptor Vγ genes is controlled by sequences immediately upstream of the Vγ genes. Immunity 9, 159–168 (1998).

    Article  CAS  PubMed  Google Scholar 

  84. Ye, S.K. et al. The IL-7 receptor controls the accessibility of the TCRγ locus by Stat5 and histone acetylation. Immunity 15, 813–823 (2001).

    Article  CAS  PubMed  Google Scholar 

  85. Hesslein, D.G. et al. Pax5 is required for recombination of transcribed, acetylated, 5′ IgH V gene segments. Genes Dev. 17, 37–42 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Mostoslavsky, R. et al. Asynchronous replication and allelic exclusion in the immune system. Nature 414, 221–225 (2001).

    Article  CAS  PubMed  Google Scholar 

  87. Singh, N. et al. Coordination of the random asynchronous replication of autosomal loci. Nature Genet. 33, 339–341 (2003).

    Article  CAS  PubMed  Google Scholar 

  88. Goldmit, M., Schlissel, M., Cedar, H. & Bergman, Y. Differential accessibility at the κ chain locus plays a role in allelic exclusion. EMBO J. 19, 5255–5261 (2002).

    Article  Google Scholar 

  89. Singh, N., Bergman, Y., Cedar, H. & Chess, A. Biallelic germline transcription at the κ immunoglobulin locus. J. Exp. Med. 197, 743–750 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Gilbert, D.M. Replication timing and transcriptional control: beyond cause and effect. Curr. Opin. Cell Biol. 14, 377–383 (2002).

    Article  CAS  PubMed  Google Scholar 

  91. Goren, A. & Cedar, H. Replicating by the clock. Nat. Rev. Mol. Cell Biol. 4, 25–32 (2003).

    Article  CAS  PubMed  Google Scholar 

  92. Zhang, J., Xu, F., Hashimshony, T., Keshet, I. & Cedar, H. Establishment of transcriptional competence in early and late S phase. Nature 420, 198–202 (2002).

    Article  CAS  PubMed  Google Scholar 

  93. Zhou, J., Ermakova, O.V., Riblet, R., Birshtein, B.K. & Schildkraut, C.L. Replication and subnuclear location dynamics of the immunoglobulin heavy-chain locus in B-lineage cells. Mol. Cell. Biol. 22, 4876–4889 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Kosak, S.T. et al. Subnuclear compartmentalization of immunoglobulin loci during lymphocyte development. Science 296, 158–162 (2002).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

I thank B. Sleckman, E. Oltz, G. Kelsoe, Y. Bergman, M. Schlissel and C. Schildkraut for helpful insights and critically reviewing the manuscript. Work in my laboratory is supported by grants from the National Institutes of Health (GM 41052 and AI 49934).

Author information

Authors and Affiliations

  1. Department of Immunology, Duke University Medical Center, Durham, 27710, North Carolina, USA

    Michael S Krangel

Authors
  1. Michael S Krangel
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Krangel, M. Gene segment selection in V(D)J recombination: accessibility and beyond. Nat Immunol 4, 624–630 (2003). https://doi.org/10.1038/ni0703-624

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni0703-624

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing