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T cell development: better living through chromatin

Nature Immunology volume 8, pages 687–694 (2007)Cite this article

Abstract

T lymphocyte development is directed by a gene-expression program that occurs in the complex nucleoprotein environment of chromatin. This review examines basic principles of chromatin regulation and evaluates ongoing progress toward understanding how the chromatin template is manipulated to control gene expression and gene recombination in developing thymocytes. Special attention is devoted to the loci encoding T cell receptors α and β, T cell coreceptors CD4 and CD8, and the enzyme terminal deoxynucleotidyl transferase. The properties of SATB1, a notable organizer of thymocyte chromatin, are also addressed.

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Figure 1: Maps of the Tcrb, Tcra, Cd4 and Cd8 loci.
Figure 2: Mechanisms of locus recruitment and regulation by Ikaros and SATB1.

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References

  1. Khorasanizadeh, S. The nucleosome: from genomic organization to genomic regulation. Cell 116, 259–272 (2004).

    CAS  PubMed  Google Scholar 

  2. Smith, C.L. & Peterson, C.L. ATP-dependent chromatin remodeling. Curr. Top. Dev. Biol. 65, 115–148 (2005).

    CAS  PubMed  Google Scholar 

  3. Mellor, J. The dynamics of chromatin remodeling at promoters. Mol. Cell 19, 147–157 (2005).

    CAS  PubMed  Google Scholar 

  4. Workman, J.L. Nucleosome displacement in transcription. Genes Dev. 20, 2009–2017 (2006).

    CAS  PubMed  Google Scholar 

  5. Li, B., Carey, J.C. & Workman, J.L. The role of chromatin during transcription. Cell 128, 707–719 (2007).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  7. Fahrner, J.A. & Baylin, S.B. Heterochromatin: stable and unstable invasions at home and abroad. Genes Dev. 17, 1805–1812 (2003).

    CAS  PubMed  Google Scholar 

  8. Wallace, J.A. & Orr-Weaver, T.L. Replication of heterochromatin: insights into mechanisms of epigenetic inheritance. Chromosoma 114, 389–402 (2005).

    CAS  PubMed  Google Scholar 

  9. Groth, A., Rocha, W., Verreault, A. & Almouzni, G. Chromatin challenges during DNA replication and repair. Cell 128, 721–733 (2007).

    CAS  PubMed  Google Scholar 

  10. Kouzarides, T. Chromatin modifications and their functions. Cell 128, 693–705 (2007).

    CAS  PubMed  Google Scholar 

  11. Shogren-Knaak, M. et al. Histone H4–K16 acetylation controls chromatin structure and protein interactions. Science 311, 844–847 (2006).

    CAS  PubMed  Google Scholar 

  12. Shilatifard, A. Chromatin modifications by methylation and ubiquitination: implications in the regulation of gene expression. Annu. Rev. Biochem. 75, 243–269 (2006).

    CAS  PubMed  Google Scholar 

  13. Sims, R.J., III & Reinberg, D. Histone H3 Lys 4 methylation: caught in a bind? Genes Dev. 20, 2779–2786 (2006).

    CAS  PubMed  Google Scholar 

  14. Saha, A., Wittmeyer, J. & Cairns, B.R. Chromatin remodelling: the industrial revolution of DNA around histones. Nat. Rev. Mol. Cell Biol. 7, 437–447 (2006).

    CAS  PubMed  Google Scholar 

  15. Ramirez-Carrozzi, V.R. et al. Selective and antagonistic functions of SWI/SNF and Mi-2β nucleosome remodeling complexes during an inflammatory response. Genes Dev. 20, 282–296 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhang, Y. et al. DNA translocation and loop formation mechanism of chromatin remodeling by SWI/SNF and RSC. Mol. Cell 24, 559–568 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Lorch, Y., Maier-Davis, B. & Kornberg, R.D. Chromatin remodeling by nucleosome disassembly in vitro. Proc. Natl. Acad. Sci. USA 103, 3090–3093 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Reinberg, D. & Sims, R.J., III. de FACTo nucleosome dynamics. J. Biol. Chem. 281, 23297–23301 (2006).

    CAS  PubMed  Google Scholar 

  19. Martin, C. & Zhang, Y. The diverse functions of histone lysine methylation. Nat. Rev. Mol. Cell Biol. 6, 838–849 (2005).

    CAS  PubMed  Google Scholar 

  20. Kosak, S.T. & Groudine, M. Form follows function: The genomic organization of cellular differentiation. Genes Dev. 18, 1371–1384 (2004).

    CAS  PubMed  Google Scholar 

  21. Misteli, T. Beyond the sequence: cellular organization of genome function. Cell 128, 787–800 (2007).

    CAS  PubMed  Google Scholar 

  22. Osborne, C.S. et al. Active genes dynamically colocalize to shared sites of ongoing transcription. Nat. Genet. 36, 1065–1071 (2004).

    CAS  PubMed  Google Scholar 

  23. Simonis, M. et al. Nuclear organization of active and inactive chromatin domains uncovered by chromosome conformation capture-on-chip (4C). Nat. Genet. 38, 1348–1354 (2006).

    CAS  PubMed  Google Scholar 

  24. Pickersgill, H. et al. Characterization of the Drosophila melanogaster genome at the nuclear lamina. Nat. Genet. 38, 1005–1014 (2006).

    CAS  PubMed  Google Scholar 

  25. Somech, R. et al. The nuclear-envelope protein and transcriptional repressor LAP2β interacts with HDAC3 at the nuclear periphery, and induces histone H4 deacetylation. J. Cell Sci. 118, 4017–4025 (2005).

    CAS  PubMed  Google Scholar 

  26. Casolari, J.M. et al. Genome-wide localization of the nuclear transport machinery couples transcriptional status and nuclear organization. Cell 117, 427–439 (2004).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  28. Ragoczy, T., Bender, M.A., Telling, A., Byron, R. & Groudine, M. The locus control region is required for association of the murine β-globin locus with engaged transcription factories during erythroid maturation. Genes Dev. 20, 1447–1457 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Fisher, A.G. & Merkenschlager, M. Gene silencing, cell fate and nuclear organisation. Curr. Opin. Genet. Dev. 12, 193–197 (2002).

    CAS  PubMed  Google Scholar 

  30. Cobb, R.M., Oestreich, K.J., Osipovich, O.A. & Oltz, E.M. Accessibility control of V(D)J recombination. Adv. Immunol. 91, 45–109 (2006).

    CAS  PubMed  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).

    CAS  PubMed  Google Scholar 

  32. Patenge, N., Elkin, S.K. & Oettinger, M.A. ATP-dependent remodeling by SWI/SNF and ISWI proteins stimulates V(D)J cleavage of 5 S arrays. J. Biol. Chem. 279, 35360–35367 (2004).

    CAS  PubMed  Google Scholar 

  33. Osipovich, O. et al. Targeted inhibition of V(D)J recombination by a histone methyltransferase. Nat. Immunol. 5, 309–316 (2004).

    CAS  PubMed  Google Scholar 

  34. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Oestreich, K.J. et al. Regulation of TCRβ gene assembly by a promoter/enhancer holocomplex. Immunity 24, 381–391 (2006).

    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).

    CAS  PubMed  Google Scholar 

  37. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Ryu, C.J. et al. The T-cell receptor β variable gene promoter is required for efficient Vβ rearrangement but not allelic exclusion. Mol. Cell. Biol. 24, 7015–7023 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Jackson, A. & Krangel, M.S. Turning T-cell receptor β recombination on and off: more questions than answers. Immunol. Rev. 209, 129–141 (2006).

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  41. Skok, J.A. et al. Reversible contraction by looping of the Tcra and Tcrb loci in rearranging thymocytes. Nat. Immunol. 8, 378–387 (2007).

    CAS  PubMed  Google Scholar 

  42. Jia, J., Kondo, M. & Zhuang, Y. Germline transcription from T-cell receptor Vβ gene is uncoupled from allelic exclusion. EMBO J. 26, 2387–2399 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Jackson, A., Kondilis, H.D., Khor, B., Sleckman, B.P. & Krangel, M.S. Regulation of T cell receptor β-allelic exclusion at a level beyond accessibility. Nat. Immunol. 6, 189–197 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Fuxa, M. et al. Pax5 induces V-to-DJ rearrangements and locus contraction of the immunoglobulin heavy-chain gene. Genes Dev. 18, 411–422 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Sayegh, C., Jhunjhunwala, S., Riblet, R. & Murre, C. Visualization of looping involving the immunoglobulin heavy-chain locus in developing B cells. Genes Dev. 19, 322–327 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Roldan, E. et al. Locus 'decontraction' and centromeric recruitment contribute to allelic exclusion of the immunoglobulin heavy-chain gene. Nat. Immunol. 6, 31–41 (2005).

    CAS  PubMed  Google Scholar 

  47. Senoo, M. et al. Increase of TCR Vβ accessibility within Eβ regulatory region influences its recombination frequency but not allelic exclusion. J. Immunol. 171, 829–835 (2003).

    CAS  PubMed  Google Scholar 

  48. Jackson, A. & Krangel, M.S. Allele-specific regulation of TCRβ variable gene segment chromatin structure. J. Immunol. 175, 5186–5191 (2005).

    CAS  PubMed  Google Scholar 

  49. 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).

    CAS  PubMed  Google Scholar 

  50. Hawwari, A. & Krangel, M.S. Regulation of TCR δ and α repertoires by local and long-distance control of variable gene segment chromatin structure. J. Exp. Med. 202, 467–472 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 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 TCRα locus accessibility. Immunity 5, 331–342 (1996).

    CAS  PubMed  Google Scholar 

  52. Hawwari, A., Bock, C. & Krangel, M.S. Regulation of TCRα gene assembly by a complex hierarchy of germline Jα promoters. Nat. Immunol. 6, 481–489 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Hawwari, A. & Krangel, M.S. Role for rearranged variable gene segments in directing secondary T cell receptor α recombination. Proc. Natl. Acad. Sci. USA 104, 903–907 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Mauvieux, L., Villey, I. & de Villartay, J-P. TEA regulates local TCR-Jα accessibility through histone acetylation. Eur. J. Immunol. 33, 2216–2222 (2003).

    CAS  PubMed  Google Scholar 

  55. Abarrategui, I. & Krangel, M.S. Regulation of T cell receptor-α gene recombination by transcription. Nat. Immunol. 7, 1109–1115 (2006).

    CAS  PubMed  Google Scholar 

  56. Zhang, Z. et al. Transcription factor Pax5 (BSAP) transactivates the RAG-mediated VH-to-DJH rearrangement of immunoglobulin genes. Nat. Immunol. 7, 616–624 (2006).

    CAS  PubMed  Google Scholar 

  57. West, K.L. et al. A direct interaction between the RAG2 C terminus and the core histones is required for efficient V(D)J recombination. Immunity 23, 203–212 (2005).

    CAS  PubMed  Google Scholar 

  58. Elkin, S.K. et al. A PHD finger motif in the C terminus of RAG2 modulates recombination activity. J. Biol. Chem. 280, 28701–28710 (2005).

    CAS  PubMed  Google Scholar 

  59. Warmflash, A. & Dinner, A.R. A model for TCR gene segment use. J. Immunol. 177, 3857–3864 (2006).

    CAS  PubMed  Google Scholar 

  60. Thiriet, C. & Hayes, J.J. Chromatin in need of a fix: phosphorylation of H2AX connects chromatin to DNA repair. Mol. Cell 18, 617–622 (2005).

    CAS  PubMed  Google Scholar 

  61. Chen, H.T. et al. Response to RAG-mediated VDJ cleavage by NBS1 and γ-H2AX. Science 290, 1962–1965 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Fernandez-Capetillo, O., Allis, C.D. & Nussenzweig, A. Phosphorylation of histone H2B at DNA double-strand breaks. J. Exp. Med. 199, 1671–1677 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Taniuchi, I., Ellmeier, W. & Littman, D.R. The CD4/CD8 lineage choice: new insights into epigenetic regulation during T cell development. Adv. Immunol. 83, 55–89 (2004).

    CAS  PubMed  Google Scholar 

  64. Taniuchi, I., Sunshine, M.J., Festenstein, R. & Littman, D.R. Evidence for distinct CD4 silencer functions at different stages of thymocyte differentiation. Mol. Cell 10, 1083–1096 (2002).

    CAS  PubMed  Google Scholar 

  65. Zou, Y.R. et al. Epigenetic silencing of CD4 in T cells committed to the cytotoxic lineage. Nat. Genet. 29, 332–336 (2001).

    CAS  PubMed  Google Scholar 

  66. Woolf, E. et al. Runx3 and Runx1 are required for CD8 T cell development during thymopoiesis. Proc. Natl. Acad. Sci. USA 100, 7731–7736 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Sato, T. et al. Dual functions of Runx proteins for reactivating CD8 and silencing CD4 at the commitment process into CD8 thymocytes. Immunity 22, 317–328 (2005).

    CAS  PubMed  Google Scholar 

  68. Taniuchi, I. et al. Differential requirements for Runx proteins in CD4 repression and epigenetic silencing during T lymphocyte development. Cell 111, 621–633 (2002).

    CAS  PubMed  Google Scholar 

  69. Telfer, J.C., Hedblom, E.E., Anderson, M.K., Laurent, M.N. & Rothenberg, E.V. Localization of the domains in Runx transcription factors required for the repression of CD4 in thymocytes. J. Immunol. 172, 4359–4370 (2004).

    CAS  PubMed  Google Scholar 

  70. Reed-Inderbitzin, E. et al. RUNX1 associates with histone deacetylases and SUV39H1 to repress transcription. Oncogene 25, 5777–5786 (2006).

    CAS  PubMed  Google Scholar 

  71. Jiang, H., Zhang, F., Kurosu, T. & Peterlin, B.M. Runx1 binds positive transcription elongation factor b and represses transcriptional elongation by RNA polymerase II: possible mechanism of CD4 silencing. Mol. Cell. Biol. 25, 10675–10683 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Feik, N. et al. Functional and molecular analysis of the double-positive stage-specific CD8 enhancer E8III during thymocyte development. J. Immunol. 174, 1513–1524 (2005).

    CAS  PubMed  Google Scholar 

  73. Bilic, I. et al. Negative regulation of CD8 expression via Cd8 enhancer-mediated recruitment of the zinc finger protein MAZR. Nat. Immunol. 7, 392–400 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Chi, T.H. et al. Reciprocal regulation of CD4/CD8 expression by SWI/SNF-like BAF complexes. Nature 418, 195–199 (2002).

    CAS  PubMed  Google Scholar 

  75. Williams, C.J. et al. The chromatin remodeler Mi-2β is required for CD4 expression and T cell development. Immunity 20, 719–733 (2004).

    CAS  PubMed  Google Scholar 

  76. Delaire, S., Huang, Y.H., Chan, S.W. & Robey, E.A. Dynamic repositioning of CD4 and CD8 genes during T cell development. J. Exp. Med. 200, 1427–1435 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Merkenschlager, M. et al. Centromeric repositioning of coreceptor loci predicts their stable silencing and the CD4/CD8 lineage choice. J. Exp. Med. 200, 1437–1444 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Su, R.C., Sridharan, R. & Smale, S.T. Assembly of silent chromatin during thymocyte development. Semin. Immunol. 17, 129–140 (2005).

    CAS  PubMed  Google Scholar 

  79. Su, R.C. et al. Dynamic assembly of silent chromatin during thymocyte maturation. Nat. Genet. 36, 502–506 (2004).

    CAS  PubMed  Google Scholar 

  80. Brown, K.E., Baxter, J., Graf, D., Merkenschlager, M. & Fisher, A.G. Dynamic repositioning of genes in the nucleus of lymphocytes preparing for cell division. Mol. Cell 3, 207–217 (1999).

    CAS  PubMed  Google Scholar 

  81. Georgopoulos, K. Haematopoietic cell-fate decisions, chromatin regulation and Ikaros. Nat. Rev. Immunol. 2, 162–174 (2002).

    CAS  PubMed  Google Scholar 

  82. Gomez-del Arco, P., Koipally, J. & Georgopoulos, K. Ikaros SUMOylation: switching out of repression. Mol. Cell. Biol. 25, 2688–2697 (2005).

    PubMed  PubMed Central  Google Scholar 

  83. Trinh, L.A. et al. Down-regulation of TDT transcription in CD4+CD8+ thymocytes by Ikaros proteins in direct competition with an Ets activator. Genes Dev. 15, 1817–1832 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Brown, K.E. et al. Association of transcriptionally silent genes with Ikaros complexes at centromeric heterochromatin. Cell 91, 845–854 (1997).

    CAS  PubMed  Google Scholar 

  85. Cobb, B.S. et al. Targeting of Ikaros to pericentromeric heterochromatin by direct DNA binding. Genes Dev. 14, 2146–2160 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Cai, S., Han, H.J. & Kohwi-Shigematsu, T. Tissue-specific nuclear architecture and gene expression regulated by SATB1. Nat. Genet. 34, 42–51 (2003).

    CAS  PubMed  Google Scholar 

  87. Alvarez, J. et al. The MAR-binding protein SATB1 orchestrates temporal and spatial expression of multiple gene during T-cell development. Genes Dev. 14, 521–535 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Yasui, D., Miyano, M., Cai, S., Varga-Weisz, P. & Kohwi-Shigematsu, T. SATB1 targets chromatin remodelling to regulate genes over long distances. Nature 419, 641–645 (2002).

    CAS  PubMed  Google Scholar 

  89. Pavan, K.P. et al. Phosphorylation of SATB1, a global gene regulator, acts as a molecular switch regulating its transcriptional activity in vivo. Mol. Cell 22, 231–243 (2006).

    Google Scholar 

  90. Cai, S., Lee, C.C. & Kohwi-Shigematsu, T. SATB1 packages densely looped, transcriptionally active chromatin for coordinated expression of cytokine genes. Nat. Genet. 38, 1278–1288 (2006).

    CAS  PubMed  Google Scholar 

  91. Seo, J., Lozano, M.M. & Dudley, J.P. Nuclear matrix binding regulates SATB1-mediated transcriptional repression. J. Biol. Chem. 280, 24600–24609 (2005).

    CAS  PubMed  Google Scholar 

  92. Harker, N. et al. The CD8α gene locus is regulated by the Ikaros family of proteins. Mol. Cell 10, 1403–1415 (2002).

    CAS  PubMed  Google Scholar 

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Acknowledgements

I thank E. Oltz, Y. Zhuang, B. Sleckman, I. Abarrategui, R. Schlimgen and H. Kondilis for comments on the manuscript, and S. Smale and I. Taniuchi for advice. Supported by the National Institutes of Health (R37 GM41052 and RO1 AI49934).

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

    Michael S Krangel

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Krangel, M. T cell development: better living through chromatin. Nat Immunol 8, 687–694 (2007). https://doi.org/10.1038/ni1484

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