Germline Transcription: A Key Regulator of Accessibility and Recombination

  • Iratxe Abarrategui
  • Michael S. KrangelEmail author
Part of the Advances in Experimental Medicine and Biology book series (volume 650)


The developmental control of V(D)J recombination is imposed at the level of chromatin accessibility of recombination signal sequences (RSSs) to the recombinase machinery. Cis-acting transcriptional regulatory elements such as promoters and enhancers play a central role in the control of accessibility in vivo. However, the molecular mechanisms by which these elements influence accessibility are still under investigation. Although accessibility for V(D)J recombination is usually accompanied by germline transcription at antigen receptor loci, the functional significance of this transcription in directing RSS accessibility has been elusive. In this chapter, we review past studies outlining the complex relationship between V(D)J recombination and transcription as well as our current understanding on how chromatin structure is regulated during gene expression. We then summarize recent work that directly addresses the functional role of transcription in V(D)J recombination.


Transcriptional Elongation Recombination Signal Sequence Allelic Exclusion PafI Complex Germline Transcription 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Cobb RM, Oestreich KJ, Osipovich OA et al. Accessibility control of V(D)J recombination. Adv Immunol 2006; 91:45–109.CrossRefPubMedGoogle Scholar
  2. 2.
    Yancopoulos GD, Alt FW. Developmentally controlled and tissue-specific expression of unrearranged VH gene segments. Cell 1985; 40:271–281.CrossRefPubMedGoogle Scholar
  3. 3.
    Fondell JD, Marcu KB. Transcription of germ line Vα segments correlates with ongoing T-cell receptor α-chain rearrangement. Mol Cell Biol 1992; 12:1480–1489.PubMedGoogle Scholar
  4. 4.
    Goldman JP, Spencer DM, Raulet DH. Ordered rearrangement of variable region genes of the T-cell receptor γ locus correlates with transcription of the unrearranged genes. J Exp Med 1993; 177:729–739.CrossRefPubMedGoogle Scholar
  5. 5.
    Schlissel MS, Corcoran LM, Baltimore D. Virus-transformed preB-cells show ordered activation but not inactivation of immunoglobulin gene rearrangement and transcription. J Exp Med 1991; 173:711–20.CrossRefPubMedGoogle Scholar
  6. 6.
    Bolland DJ, Wood AL, Johnston CM et al. Antisense intergenic transcription in V(D)J recombination. Nat Immunol 2004; 5:630–637.CrossRefPubMedGoogle Scholar
  7. 7.
    Blackwell TK, Moore MW, Yancopoulos GD et al. Recombination between immunoglobulin variable region gene segments is enhanced by transcription. Nature 1986; 324:585–589.CrossRefPubMedGoogle Scholar
  8. 8.
    Schlissel MS, Baltimore D. Activation of immunoglobulin kappa gene rearrangement correlates with induction of germline kappa gene transcription. Cell 1989; 58:1001–1007.CrossRefPubMedGoogle Scholar
  9. 9.
    Oltz EM, Alt FW, Lin WC et al. A V(D)J recombinase-inducible B-cell line: role of transcriptional enhancer elements in directing V(D)J recombination. Mol Cell Biol 1993; 13:6223–6230.PubMedGoogle Scholar
  10. 10.
    Sun T, Storb U. Insertion of phosphoglycerine kinase (PGK)-neo 5′ of Jλ1 dramatically enhances VJλ1 rearrangement. J Exp Med 2001; 193:699–712.CrossRefPubMedGoogle Scholar
  11. 11.
    Romanow WJ, Langerak AW, Goebel P et al. E2A and EBF act in synergy with the V(D)J recombinase to generate a diverse immunoglobulin repertoire in nonlymphoid cells. Mol Cell 2000; 5:343–353.CrossRefPubMedGoogle Scholar
  12. 12.
    Ghosh JK, Romanow WJ, Murre C. Induction of a diverse T-cell receptor Ψ/δ repertoire by the helix-loop-helix proteins E2A and HEB in nonlymphoid cells. J Exp Med 2001; 193:769–775.CrossRefPubMedGoogle Scholar
  13. 13.
    Casellas R, Jankovic M, Meyer G et al. OcaB is required for normal transcription and V(D)J recombination of a subset of immunoglobulin kappa genes. Cell 2002; 110:575–585.CrossRefPubMedGoogle Scholar
  14. 14.
    Bertolino E, Reddy K, Medina KL et al. Regulation of interleukin 7-dependent immunoglobulin heavy-chain variable gene rearrangements by transcription factor STAT5. Nat Immunol 2005; 6:836–843.CrossRefPubMedGoogle Scholar
  15. 15.
    Ye SK, Agata Y, Lee HC et al. The IL-7 receptor controls the accessibility of the TCRγ locus by Stat5 and histone acetylation. Immunity 2001; 15:813–823.CrossRefPubMedGoogle Scholar
  16. 16.
    Zhao H, Nguyen H, Kang J. Interleukin 15 controls the generation of the restricted T-cell receptor repertoire of γδ intestinal intraepithelial lymphocytes. Nat Immunol 2005;6:1263–1271.CrossRefPubMedGoogle Scholar
  17. 17.
    Hesslein DG, Pflugh DL, Chowdhury D et al. Pax5 is required for recombination of transcribed, acetylated, 5′ IgH V gene segments. Genes Dev 2003; 17:37–42.CrossRefPubMedGoogle Scholar
  18. 18.
    Fuxa M, Skok J, Souabni A et al. Pax5 induces V-to-DJ rearrangements and locus contraction of the immunoglobulin heavy-chain gene. Genes Dev 2004; 18:411–422.CrossRefPubMedGoogle Scholar
  19. 19.
    Zhang Z, Espinoza CR, Yu Z et al. Transcription factor Pax5 (BSAP) transactivates the RAG-mediated VH-to-DJH rearrangement of immunoglobulin genes. Nat Immunol 2006; 7:616–624.CrossRefPubMedGoogle Scholar
  20. 20.
    Okada A, Mendelsohn M, Alt F. Differential activation of transcription versus recombination of transgenic T-cell receptor β variable region gene segments in B and T lineage cells. J Exp Med 1994; 180:261–272.CrossRefPubMedGoogle Scholar
  21. 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 1995; 15:3217–3226.PubMedGoogle Scholar
  22. 22.
    Tripathi RK, Mathieu N, Spicuglia S et al. Definition of a T-cell receptor β gene core enhancer of V(D) J recombination by transgenic mapping. Mol Cell Biol 2000; 20:42–53.CrossRefPubMedGoogle Scholar
  23. 23.
    Jia J, Kondo M, Zhuang Y. Germline transcription from T-cell receptor Vβ gene is uncoupled from allelic exclusion. EMBO J 2007; 26:2387–2399.CrossRefPubMedGoogle Scholar
  24. 24.
    Jackson A, Kondilis HD, Khor B et al. Regulation of T-cell receptor β allelic exclusion at a level beyond accessibility. Nat Immunol 2005; 6:189–197.CrossRefPubMedGoogle Scholar
  25. 25.
    Senoo M, Wang L, Suzuki D et al. Increase of TCR Vβ accessibility within Eβ regulatory region influences its recombination frequency but not allelic exclusion. J Immunol 2003; 171:829–835.PubMedGoogle Scholar
  26. 26.
    Stanhope-Baker P, Hudson KM, Shaffer AL et al. Cell type-specific chromatin structure determines the targeting of V(D)J recombinase activity in vitro. Cell 1996; 85:887–897.CrossRefPubMedGoogle Scholar
  27. 27.
    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 1998; 18:6253–6264.PubMedGoogle Scholar
  28. 28.
    Cherry SR, Baltimore D. Chromatin remodeling directly activates V(D)J recombination. Proc Natl Acad Sci USA 1999; 96:10788–10793.CrossRefPubMedGoogle Scholar
  29. 29.
    Whitehurst CE, 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 1999; 10:313–322.CrossRefPubMedGoogle Scholar
  30. 30.
    Mathieu N, Hempel WM, Spicuglia S et al. 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 2000; 192:625–636.CrossRefPubMedGoogle Scholar
  31. 31.
    Spicuglia S, Kumar S, Yeh JH et al. Promoter activation by enhancer-dependent and-independent loading of activator and coactivator complexes. Mol Cell 2002; 10:1479–1487.CrossRefPubMedGoogle Scholar
  32. 32.
    Oestreich KJ, Cobb RM, Pierce S et al. Regulation of TCRβ gene assembly by a promoter/enhancer holocomplex. Immunity 2006; 24:381–391.CrossRefPubMedGoogle Scholar
  33. 33.
    Sikes ML, Meade A, Tripathi R et al. Regulation of V(D)J recombination: a dominant role for promoter positioning in gene segment accessibility. Proc Natl Acad Sci USA 2002; 99:12309–12314.CrossRefPubMedGoogle Scholar
  34. 34.
    Osipovich O, Cobb RM, Oestreich KJ et al. Essential function for SWI-SNF chromatin remodeling complexes in the promoter-directed assembly of Tcrb genes. Nat Immunol 2007; 8:809–816.CrossRefPubMedGoogle Scholar
  35. 35.
    Misteli T. Beyond the sequence: cellular organization of genome function. Cell 2007; 128:787–800.CrossRefPubMedGoogle Scholar
  36. 36.
    Khorasanizadeh S. The nucleosome: from genomic organization to genomic regulation. Cell 2004; 116:259–272.CrossRefPubMedGoogle Scholar
  37. 37.
    Tremethick DJ. Higher-order structures of chromatin: the elusive 30 nm fiber. Cell 2007; 128:651–654.CrossRefPubMedGoogle Scholar
  38. 38.
    Kouzarides T. Chromatin modifications and their function. Cell 2007; 128:693–705.CrossRefPubMedGoogle Scholar
  39. 39.
    Lee KK, Workman JL. Histone acetyltransferase complexes: one size doesn’t fit all. Nat Rev Mol Cell Biol 2007; 8:284–295.CrossRefPubMedGoogle Scholar
  40. 40.
    Shi Y, Whetstine JR. Dynamic regulation of histone lysine methylation by demethylases. Mol Cell 2007; 25:1–14.CrossRefPubMedGoogle Scholar
  41. 41.
    Li B, Carey M, Workman JL. The role of chromatin during transcription. Cell 2007; 128:707–719.CrossRefPubMedGoogle Scholar
  42. 42.
    Ruthenburg AJ, Allis CD, Wysocka J. Methylation of lysine 4 on histone H3: intricacy of writing and reading a single epigenetic mark. Mol Cell 2007; 25:15–30.CrossRefPubMedGoogle Scholar
  43. 43.
    Shogren-Knaak M, Ishii H, Sun JM et al. Histone H4-K16 acetylation controls chromatin structure and protein interactions. Science 2006; 311:844–847.CrossRefPubMedGoogle Scholar
  44. 44.
    Lachner M, O’Carroll D, Rea S et al. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 2001; 410:116–120.CrossRefPubMedGoogle Scholar
  45. 45.
    Shi X, Hong T, Walter KL et al. ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression. Nature 2006; 442:96–99.CrossRefPubMedGoogle Scholar
  46. 46.
    Taverna SD, Ilin S, Rogers RS et al. Yngl PHD finger binding to H3 trimethylated at K4 promotes NuA3 HAT activity at K14 of H3 and transcription at a subset of targeted ORFs. Mol Cell 2006; 24:785–796.CrossRefPubMedGoogle Scholar
  47. 47.
    Wysocka J, Swigut T, Xiao H et al. A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling. Nature 2006; 442:86–90.PubMedGoogle Scholar
  48. 48.
    Li B, Gogol M, Carey M et al. Combined action of PHD and Chromodomains directs the Rpd3S HDAC to transcribed chromatin. Science 2007; 316:1050–1054.CrossRefPubMedGoogle Scholar
  49. 49.
    Saha A, Wittmeyer J, Cairns BR. Chromatin remodelling: the industrial revolution of DNA around histones. Nat Rev Mol Cell Biol 2006; 7:437–447.CrossRefPubMedGoogle Scholar
  50. 50.
    Smith CL, Peterson CL. ATP-dependent chromatin remodeling. Curr Top Dev Biol 2005; 65:115–148.CrossRefPubMedGoogle Scholar
  51. 51.
    Bruno M, Flaus A, Stockdale C et al. Histone H2A/H2B dimer exchange by ATP-dependent chromatin remodeling activities. Mol Cell 2003; 12:1599–1606.CrossRefPubMedGoogle Scholar
  52. 52.
    Workman JL. Nucleosome displacement in transcription. Genes Dev 2006; 20:2009–2017.CrossRefPubMedGoogle Scholar
  53. 53.
    Hassan AH, Neely KE, Workman JL. Histone acetyltransferase complexes stabilize SWI/SNF binding to promoter nucleosomes. Cell 2001; 104:817–827.CrossRefPubMedGoogle Scholar
  54. 54.
    Sims RJ 3rd, Belotserkovskaya R, Reinberg D. Elongation by RNA polymerase II: the short and long of it. Genes Dev 2004; 18:2437–2468.CrossRefPubMedGoogle Scholar
  55. 55.
    Krogan NJ, Dover J, Wood A et al. The Paf1 complex is required for histone H3 methylation by COMPASS and Dot1p: linking transcriptional elongation to histone methylation. Mol Cell 2003; 11:721–729.CrossRefPubMedGoogle Scholar
  56. 56.
    Wood A, Schneider J, Dover J et al. The Paf1 complex is essential for histone monoubiquitination by the Rad6-Bre1 complex, which signals for histone methylation by COMPASS and Dot1p. J Biol Chem 2003; 278:34739–34742.CrossRefPubMedGoogle Scholar
  57. 57.
    Xiao T, Hall H, Kizer KO et al. Phosphorylation of RNA polymerase II CTD regulates H3 methylation in yeast. Genes Dev 2003; 17:654–663.CrossRefPubMedGoogle Scholar
  58. 58.
    Govind CK, Zhang F, Qiu H et al. Gcn5 promotes acetylation, eviction and methylation of nucleosomes in transcribed coding regions. Mol Cell 2007; 25:31–42.CrossRefPubMedGoogle Scholar
  59. 59.
    Pavri R, Zhu B, Li G et al. Histone H2B monoubiquitination functions cooperatively with FACT to regulate elongation by RNA polymerase II. Cell 2006; 125:703–717.CrossRefPubMedGoogle Scholar
  60. 60.
    Carrozza MJ, Li B, Florens L et al. Histone H3 methylation by Set2 directs deacetylation of coding regions by Rpd3S to suppress spurious intragenic transcription. Cell 2005; 123:581–592.CrossRefPubMedGoogle Scholar
  61. 61.
    Joshi AA, Struhl K. Eaf3 chromodomain interaction with methylated H3-K36 links histone deacetylation to Pol II elongation. Mol Cell 2005; 20:971–978.CrossRefPubMedGoogle Scholar
  62. 62.
    Belotserkovskaya R, Oh S, Bondarenko VA et al. FACT facilitates transcription-dependent nucleosome alteration. Science 2003; 301:1090–1093.CrossRefPubMedGoogle Scholar
  63. 63.
    Schwabish MA, Struhl K. Asf1 mediates histone eviction and deposition during elongation by RNA polymerase II. Mol Cell 2006; 22:415–422.CrossRefPubMedGoogle Scholar
  64. 64.
    Carey M, Li B, Workman JL. RSC exploits histone acetylation to abrogate the nucleosomal block to RNA polymerase II elongation. Mol Cell 2006; 24:481–487.CrossRefPubMedGoogle Scholar
  65. 65.
    Corey LL, Weirich CS, Benjamin IJ et al. Localized recruitment of a chromatin-remodeling activity by an activator in vivo drives transcriptional elongation. Genes Dev 2003; 17:1392–1401.CrossRefPubMedGoogle Scholar
  66. 66.
    Krangel MS, Carabana J, Abarrategui I et al. Enforcing order within a complex locus: current perspectives on the control of V(D)J recombination at the murine T-cell receptor α/δ locus. Immunol Rev 2004; 200:224–232.CrossRefPubMedGoogle Scholar
  67. 67.
    Sleckman BP, Bardon CG, Ferrini R et al. Function of the TCRα enhancer in αβ and γδ T-cells. Immunity 1997; 7:505–515.CrossRefPubMedGoogle Scholar
  68. 68.
    Villey I, Caillol D, Selz F et al. Defect in rearrangement of the most 5′ TCR-Jα following targeted deletion of T early alpha (TEA): implications for TCRα locus accessibility. Immunity 1996; 5:331–342.CrossRefPubMedGoogle Scholar
  69. 69.
    Hawwari A, Bock C, Krangel MS. Regulation of T-cell receptor-α gene assembly by a complex hierarchy of germline Jα promoters. Nat Immunol 2005; 6:481–489.CrossRefPubMedGoogle Scholar
  70. 70.
    Buch T, Rieux-Laucat F, Forster I et al. Failure of HY-specific thymocytes to escape negative selection by receptor editing. Immunity 2002; 16:707–718.CrossRefPubMedGoogle Scholar
  71. 71.
    Wang F, Huang CY, Kanagawa O. Rapid deletion of rearranged T-cell antigen receptor (TCR) Vα-Jα segment by secondary rearrangement in the thymus: role of continuous rearrangement of TCRα chain gene and positive selection in the T-cell repertoire formation. Proc Natl Acad Sci USA 1998; 95:11834–11839.CrossRefPubMedGoogle Scholar
  72. 72.
    Hawwari A, Krangel MS. Role for rearranged variable gene segments in directing secondary T-cell receptor-α recombination. Proc Natl Acad Sci USA 2007; 104:903–907.CrossRefPubMedGoogle Scholar
  73. 73.
    Mauvieux L, Villey I, de Villartay J-P. TEA regulates local TCR-Jα accessibility through histone acetylation. Eur J Immunol 2003; 33:2216–2222.CrossRefPubMedGoogle Scholar
  74. 74.
    Abarrategui I, Krangel MS. Regulation of T-cell receptor-α gene recombination by transcription. Nat Immunol 2006; 7:1109–1115.CrossRefPubMedGoogle Scholar
  75. 75.
    Abarrategui I, Krangel MS. Noncoding transcription controls downstream promoters to regulate T-cell receptor α recombination. EMBO J 2007; 26:4380–4390.CrossRefPubMedGoogle Scholar
  76. 76.
    Bolland DJ, Wood AL, Afshar R et al. Antisense intergenic transcription precedes Igh D-to-J recombination and is controlled by the intronic enhancer Eμ. Mol Cell Biol 2007; 27:5523–5533.CrossRefPubMedGoogle Scholar
  77. 77.
    Elkin SK, Ivanov D, Ewalt M et al. A PHD finger motif in the C terminus of RAG2 modulates recombination activity. J Biol Chem 2005; 280:28701–28710.CrossRefPubMedGoogle Scholar
  78. 78.
    West KL, Singha NC, De Ioannes P et al. A direct interaction between the RAG2 C terminus and the core histones is required for efficient V(D)J recombination. Immunity 2005; 23:203–212.CrossRefPubMedGoogle Scholar
  79. 79.
    Tanny JC, Erdjument-Bromage H, Tempst P et al. Ubiquitylation of histone H2B controls RNA polymerase II transcription elongation independently of histone H3 methylation. Genes Dev 2007; 21:835–847.CrossRefPubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2009

Authors and Affiliations

  1. 1.Centre for EpigeneticsBiotech Research and Innovation CentreCopenhagenDenmark
  2. 2.Department of ImmunologyDuke University Medical CenterDurhamUSA

Personalised recommendations