The Epigenetic Landscape of Lineage Choice: Lessons From the Heritability of Cd4 and Cd8 Expression

  • Manolis Gialitakis
  • MacLean Sellars
  • Dan R. LittmanEmail author
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 356)


Developing αβ T cells choose between the helper and cytotoxic lineages, depending upon the specificity of their T cell receptors for MHC molecules. The expression of the CD4 co-receptor on helper cells and the CD8 co-receptor on cytotoxic cells is intimately linked to this decision, and their regulation at the transcriptional level has been the subject of intense study to better understand lineage choice. Indeed, as the fate of developing T cells is decided, the expression status of these genes is accordingly locked. Genetic models have revealed important transcriptional elements and the ability to manipulate these elements in the framework of development has added a new perspective on the temporal nature of their function and the epigenetic maintenance of gene expression. We examine here novel insights into epigenetic mechanisms that have arisen through the study of these genes.


Double Negative Double Positive Cell Double Positive Double Positive Thymocyte Double Negative Cell 
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.


  1. Adlam M, Duncan DD, Ng DK, Siu G (1997) Positive selection induces CD4 promoter and enhancer function. Int Immunol 9:877–887PubMedCrossRefGoogle Scholar
  2. Adlam M, Siu G (2003) Hierarchical interactions control CD4 gene expression during thymocyte development. Immunity 18:173–184PubMedCrossRefGoogle Scholar
  3. Agalioti T, Lomvardas S, Parekh B, Yie J, Maniatis T, Thanos D (2000) Ordered recruitment of chromatin modifying and general transcription factors to the IFN-beta promoter. Cell 103:667–678PubMedCrossRefGoogle Scholar
  4. Allfrey VG (1966) Structural modifications of histones and their possible role in the regulation of ribonucleic acid synthesis. Proc Can Cancer Conf 6:313-335Google Scholar
  5. Bachman KE, Park BH, Rhee I, Rajagopalan H, Herman JG, Baylin SB, Kinzler KW, Vogelstein B (2003) Histone modifications and silencing prior to DNA methylation of a tumor suppressor gene. Cancer Cell 3:89–95PubMedCrossRefGoogle Scholar
  6. Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, Wei G, Chepelev I, Zhao K (2007) High-resolution profiling of histone methylations in the human genome. Cell 129:823–837PubMedCrossRefGoogle Scholar
  7. Bartke T, Vermeulen M, Xhemalce B, Robson SC, Mann M, Kouzarides T (2010) Nucleosome-interacting proteins regulated by DNA and histone methylation. Cell 143:470–484PubMedCrossRefGoogle Scholar
  8. Bilic I, Koesters C, Unger B, Sekimata M, Hertweck A, Maschek R, Wilson CB, Ellmeier W (2006) Negative regulation of CD8 expression via Cd8 enhancer-mediated recruitment of the zinc finger protein MAZR. Nat Immunol 7:392–400PubMedCrossRefGoogle Scholar
  9. Blum MD, Wong GT, Higgins KM, Sunshine MJ, Lacy E (1993) Reconstitution of the subclass-specific expression of CD4 in thymocytes and peripheral T cells of transgenic mice: identification of a human CD4 enhancer. J Exp Med 177:1343–1358PubMedCrossRefGoogle Scholar
  10. Brickner DG, Cajigas I, Fondufe-Mittendorf Y, Ahmed S, Lee PC, Widom J, Brickner JH (2007) H2A.Z-mediated localization of genes at the nuclear periphery confers epigenetic memory of previous transcriptional state. PLoS Biol 5:e81Google Scholar
  11. Brown CJ, Willard HF (1994) The human X-inactivation centre is not required for maintenance of X-chromosome inactivation. Nature 368:154–156PubMedCrossRefGoogle Scholar
  12. Bruniquel D, Borie N, Hannier S, Triebel F (1998) Regulation of expression of the human lymphocyte activation gene-3 (LAG-3) molecule, a ligand for MHC class II. Immunogenetics 48:116–124PubMedCrossRefGoogle Scholar
  13. Bruniquel D, Schwartz RH (2003) Selective, stable demethylation of the interleukin-2 gene enhances transcription by an active process. Nat Immunol 4:235–240PubMedCrossRefGoogle Scholar
  14. Bruno L, Mazzarella L, Hoogenkamp M, Hertweck A, Cobb BS, Sauer S, Hadjur S, Leleu M, Naoe Y, Telfer JC et al (2009) Runx proteins regulate Foxp3 expression. J Exp Med 206:2329–2337PubMedCrossRefGoogle Scholar
  15. Campos EI, Reinberg D (2009) Histones: annotating chromatin. Annu Rev Genet 43:559–599PubMedCrossRefGoogle Scholar
  16. Carbone AM, Marrack P, Kappler JW (1988) Demethylated CD8 gene in CD4+ T cells suggests that CD4+ cells develop from CD8+ precursors. Science 242:1174–1176PubMedCrossRefGoogle Scholar
  17. Chi TH, Wan M, Lee PP, Akashi K, Metzger D, Chambon P, Wilson CB, Crabtree GR (2003) Sequential roles of Brg, the ATPase subunit of BAF chromatin remodeling complexes, in thymocyte development. Immunity 19:169–182PubMedCrossRefGoogle Scholar
  18. Chi TH, Wan M, Zhao K, Taniuchi I, Chen L, Littman DR, Crabtree GR (2002) Reciprocal regulation of CD4/CD8 expression by SWI/SNF-like BAF complexes. Nature 418:195–199PubMedCrossRefGoogle Scholar
  19. Chong MM, Simpson N, Ciofani M, Chen G, Collins A, Littman DR (2010) Epigenetic propagation of CD4 expression is established by the Cd4 proximal enhancer in helper T cells. Genes Dev 24:659–669PubMedCrossRefGoogle Scholar
  20. Ciofani M, Zuniga-Pflucker JC (2010) Determining gammadelta versus alphass T cell development. Nat Rev Immunol 10:657–663PubMedGoogle Scholar
  21. Collins A, Hewitt SL, Chaumeil J, Sellars M, Micsinai M, Allinne J, Parisi F, Nora EP, Bolland DJ, Corcoran AE et al (2011) RUNX transcription factor-mediated association of Cd4 and Cd8 enables coordinate gene regulation. Immunity 34:303–314PubMedCrossRefGoogle Scholar
  22. Csankovszki G, Panning B, Bates B, Pehrson JR, Jaenisch R (1999) Conditional deletion of Xist disrupts histone macroH2A localization but not maintenance of X inactivation. Nat Genet 22:323–324PubMedCrossRefGoogle Scholar
  23. Delaire S, Huang YH, Chan SW, Robey EA (2004) Dynamic repositioning of CD4 and CD8 genes during T cell development. J Exp Med 200:1427–1435PubMedCrossRefGoogle Scholar
  24. Devine L, Kieffer LJ, Aitken V, Kavathas PB (2000) Human CD8 beta, but not mouse CD8 beta, can be expressed in the absence of CD8 alpha as a beta beta homodimer. J Immunol 164:833–838PubMedGoogle Scholar
  25. Egawa T, Littman DR (2008) ThPOK acts late in specification of the helper T cell lineage and suppresses Runx-mediated commitment to the cytotoxic T cell lineage. Nat Immunol 9:1131–1139PubMedCrossRefGoogle Scholar
  26. Egawa T, Littman DR (2011) The transcription factor AP4 modulates reversible and epigenetic silencing of the Cd4 gene. Proc Natl Acad Sci USA 108:14873–14878PubMedCrossRefGoogle Scholar
  27. Egawa T, Tillman RE, Naoe Y, Taniuchi I, Littman DR (2007) The role of the Runx transcription factors in thymocyte differentiation and in homeostasis of naive T cells. J Exp Med 204:1945–1957PubMedCrossRefGoogle Scholar
  28. Ellmeier W, Sunshine MJ, Losos K, Hatam F, Littman DR (1997) An enhancer that directs lineage-specific expression of CD8 in positively selected thymocytes and mature T cells. Immunity 7:537–547PubMedCrossRefGoogle Scholar
  29. Ellmeier W, Sunshine MJ, Losos K, Littman DR (1998) Multiple developmental stage-specific enhancers regulate CD8 expression in developing thymocytes and in thymus-independent T cells. Immunity 9:485–496PubMedCrossRefGoogle Scholar
  30. Ellmeier W, Sunshine MJ, Maschek R, Littman DR (2002) Combined deletion of CD8 locus cis-regulatory elements affects initiation but not maintenance of CD8 expression. Immunity 16:623–634PubMedCrossRefGoogle Scholar
  31. Feik N, Bilic I, Tinhofer J, Unger B, Littman DR, Ellmeier W (2005) Functional and molecular analysis of the double-positive stage-specific CD8 enhancer E8III during thymocyte development. J Immunol 174:1513–1524PubMedGoogle Scholar
  32. Ficz G, Branco MR, Seisenberger S, Santos F, Krueger F, Hore TA, Marques CJ, Andrews S, Reik W (2011) Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation. Nature 473:398–402PubMedCrossRefGoogle Scholar
  33. Filion GJ, van Bemmel JG, Braunschweig U, Talhout W, Kind J, Ward LD, Brugman W, de Castro IJ, Kerkhoven RM, Bussemaker HJ et al (2010) Systematic protein location mapping reveals five principal chromatin types in Drosophila cells. Cell 143:212–224PubMedCrossRefGoogle Scholar
  34. Fischle W, Tseng BS, Dormann HL, Ueberheide BM, Garcia BA, Shabanowitz J, Hunt DF, Funabiki H, Allis CD (2005) Regulation of HP1-chromatin binding by histone H3 methylation and phosphorylation. Nature 438:1116–1122PubMedCrossRefGoogle Scholar
  35. Fodor BD, Shukeir N, Reuter G, Jenuwein T (2010) Mammalian Su(var) genes in chromatin control. Annu Rev Cell Dev Biol 26:471–501PubMedCrossRefGoogle Scholar
  36. Foster SL, Hargreaves DC, Medzhitov R (2007) Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature 447:972–978PubMedGoogle Scholar
  37. Frankel N, Davis GK, Vargas D, Wang S, Payre F, Stern DL (2010) Phenotypic robustness conferred by apparently redundant transcriptional enhancers. Nature 466:490–493PubMedCrossRefGoogle Scholar
  38. Fuks F, Burgers WA, Brehm A, Hughes-Davies L, Kouzarides T (2000) DNA methyltransferase Dnmt1 associates with histone deacetylase activity. Nat Genet 24:88–91PubMedCrossRefGoogle Scholar
  39. Fung-Leung WP, Schilham MW, Rahemtulla A, Kundig TM, Vollenweider M, Potter J, van Ewijk W, Mak TW (1991) CD8 is needed for development of cytotoxic T cells but not helper T cells. Cell 65:443–449PubMedCrossRefGoogle Scholar
  40. Garefalaki A, Coles M, Hirschberg S, Mavria G, Norton T, Hostert A, Kioussis D (2002) Variegated expression of CD8 alpha resulting from in situ deletion of regulatory sequences. Immunity 16:635–647PubMedCrossRefGoogle Scholar
  41. Gialitakis M, Arampatzi P, Makatounakis T, Papamatheakis J (2010) Gamma interferon-dependent transcriptional memory via relocalization of a gene locus to PML nuclear bodies. Mol Cell Biol 30:2046–2056PubMedCrossRefGoogle Scholar
  42. Hamerman JA, Page ST, Pullen AM (1997) Distinct methylation states of the CD8 beta gene in peripheral T cells and intraepithelial lymphocytes. J Immunol 159:1240–1246PubMedGoogle Scholar
  43. Hanna Z, Simard C, Laperriere A, Jolicoeur P (1994) Specific expression of the human CD4 gene in mature CD4+ CD8- and immature CD4+ CD8+ T cells and in macrophages of transgenic mice. Mol Cell Biol 14:1084–1094PubMedGoogle Scholar
  44. Hansen KH, Bracken AP, Pasini D, Dietrich N, Gehani SS, Monrad A, Rappsilber J, Lerdrup M, Helin K (2008) A model for transmission of the H3K27me3 epigenetic mark. Nat Cell Biol 10:1291–1300PubMedCrossRefGoogle Scholar
  45. He HH, Meyer CA, Shin H, Bailey ST, Wei G, Wang Q, Zhang Y, Xu K, Ni, M, Lupien M et al (2010) Nucleosome dynamics define transcriptional enhancers. Nat Genet 42:343–347PubMedCrossRefGoogle Scholar
  46. He X, Dave VP, Zhang Y, Hua X, Nicolas E, Xu W, Roe BA, Kappes DJ (2005) The zinc finger transcription factor Th-POK regulates CD4 versus CD8 T-cell lineage commitment. Nature 433:826–833PubMedCrossRefGoogle Scholar
  47. Heintzman ND, Stuart RK, Hon G, Fu Y, Ching CW, Hawkins RD, Barrera LO, Van Calcar S, Qu C, Ching KA et al (2007) Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat Genet 39:311–318PubMedCrossRefGoogle Scholar
  48. Hernandez-Hoyos G, Anderson MK, Wang C, Rothenberg EV, Alberola-Ila J (2003) GATA-3 expression is controlled by TCR signals and regulates CD4/CD8 differentiation. Immunity 19:83–94PubMedCrossRefGoogle Scholar
  49. Hostert A, Garefalaki A, Mavria G, Tolaini M, Roderick K, Norton T, Mee PJ, Tybulewicz VL, Coles M, Kioussis D (1998) Hierarchical interactions of control elements determine CD8alpha gene expression in subsets of thymocytes and peripheral T cells. Immunity 9:497–508PubMedCrossRefGoogle Scholar
  50. Hostert A, Tolaini M, Festenstein R, McNeill L, Malissen B, Williams O, Zamoyska R, Kioussis D (1997a) A CD8 genomic fragment that directs subset-specific expression of CD8 in transgenic mice. J Immunol 158:4270–4281PubMedGoogle Scholar
  51. Hostert A, Tolaini M, Roderick K, Harker N, Norton T, Kioussis D (1997b) A region in the CD8 gene locus that directs expression to the mature CD8 T cell subset in transgenic mice. Immunity 7:525–536PubMedCrossRefGoogle Scholar
  52. Jeon Y, Lee JT (2011) YY1 Tethers Xist RNA to the Inactive X Nucleation Center. Cell 146:119–133PubMedCrossRefGoogle Scholar
  53. Ji H, Ehrlich LI, Seita J, Murakami P, Doi A, Lindau P, Lee H, Aryee MJ, Irizarry RA, Kim K et al (2010) Comprehensive methylome map of lineage commitment from haematopoietic progenitors. Nature 467:338–342PubMedCrossRefGoogle Scholar
  54. Jiang H, Peterlin BM (2008) Differential chromatin looping regulates CD4 expression in immature thymocytes. Mol Cell Biol 28:907–912PubMedCrossRefGoogle Scholar
  55. Jiang H, Zhang F, Kurosu T, Peterlin BM (2005) Runx1 binds positive transcription elongation factor b and represses transcriptional elongation by RNA polymerase II: possible mechanism of CD4 silencing. Mol Cell Biol 25:10675–10683PubMedCrossRefGoogle Scholar
  56. Jones ME, Zhuang Y (2007) Acquisition of a functional T cell receptor during T lymphocyte development is enforced by HEB and E2A transcription factors. Immunity 27:860–870PubMedCrossRefGoogle Scholar
  57. Kieffer LJ, Bennett JA, Cunningham AC, Gladue RP, McNeish J, Kavathas PB, Hanke JH (1996) Human CD8 alpha expression in NK cells but not cytotoxic T cells of transgenic mice. Int Immunol 8:1617–1626PubMedCrossRefGoogle Scholar
  58. Kieffer LJ, Yan L, Hanke JH, Kavathas PB (1997) Appropriate developmental expression of human CD8 beta in transgenic mice. J Immunol 159:4907–4912PubMedGoogle Scholar
  59. Killeen N, Sawada S, Littman DR (1993) Regulated expression of human CD4 rescues helper T cell development in mice lacking expression of endogenous CD4. EMBO J 12:1547–1553PubMedGoogle Scholar
  60. Lal G, Zhang N, van der Touw W, Ding Y, Ju W, Bottinger EP, Reid SP, Levy DE, Bromberg JS (2009) Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. J Immunol 182:259–273PubMedGoogle Scholar
  61. Lee CK, Shibata Y, Rao B, Strahl BD, Lieb JD (2004) Evidence for nucleosome depletion at active regulatory regions genome-wide. Nat Genet 36:900–905PubMedCrossRefGoogle Scholar
  62. Lee GR, Spilianakis CG, Flavell RA (2005) Hypersensitive site 7 of the TH2 locus control region is essential for expressing TH2 cytokine genes and for long-range intrachromosomal interactions. Nat Immunol 6:42–48PubMedCrossRefGoogle Scholar
  63. Lee JS, Smith E, Shilatifard A (2010) The language of histone crosstalk. Cell 142:682–685PubMedCrossRefGoogle Scholar
  64. Lee PP, Fitzpatrick DR, Beard C, Jessup HK, Lehar S, Makar KW, Perez-Melgosa M, Sweetser MT, Schlissel MS, Nguyen S et al (2001) A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival. Immunity 15:763-774PubMedCrossRefGoogle Scholar
  65. Leung RK, Thomson K, Gallimore A, Jones E, Van den Broek M, Sierro S, Alsheikhly AR, McMichael A, Rahemtulla A (2001) Deletion of the CD4 silencer element supports a stochastic mechanism of thymocyte lineage commitment. Nat Immunol 2:1167–1173PubMedCrossRefGoogle Scholar
  66. Levanon D, Goldstein RE, Bernstein Y, Tang H, Goldenberg D, Stifani S, Paroush Z, Groner Y (1998) Transcriptional repression by AML1 and LEF-1 is mediated by the TLE/Groucho corepressors. Proc Natl Acad Sci USA 95:11590–11595PubMedCrossRefGoogle Scholar
  67. Lomvardas S, Thanos D (2001) Nucleosome sliding via TBP DNA binding in vivo. Cell 106:685–696PubMedCrossRefGoogle Scholar
  68. Manjunath N, Shankar P, Stockton B, Dubey PD, Lieberman J, von Andrian UH (1999) A transgenic mouse model to analyze CD8(+) effector T cell differentiation in vivo. Proc Natl Acad Sci U S A 96:13932–13937PubMedCrossRefGoogle Scholar
  69. Margueron R, Justin N, Ohno K, Sharpe ML, Son J, Drury WJ, 3rd, Voigt P, Martin SR, Taylor WR, De Marco V et al (2009) Role of the polycomb protein EED in the propagation of repressive histone marks. Nature 461:762–767PubMedCrossRefGoogle Scholar
  70. Mateescu B, Bourachot B, Rachez C, Ogryzko V, Muchardt C (2008) Regulation of an inducible promoter by an HP1beta-HP1gamma switch. EMBO Rep 9:267–272PubMedCrossRefGoogle Scholar
  71. Merkenschlager M, Amoils S, Roldan E, Rahemtulla A, O’Connor E, Fisher AG, Brown KE (2004) Centromeric repositioning of coreceptor loci predicts their stable silencing and the CD4/CD8 lineage choice. J Exp Med 200:1437–1444PubMedCrossRefGoogle Scholar
  72. Murayama A, Sakura K, Nakama M, Yasuzawa-Tanaka K, Fujita E, Tateishi Y, Wang Y, Ushijima T, Baba T, Shibuya K et al (2006) A specific CpG site demethylation in the human interleukin 2 gene promoter is an epigenetic memory. EMBO J 25:1081–1092PubMedCrossRefGoogle Scholar
  73. Muroi S, Naoe Y, Miyamoto C, Akiyama K, Ikawa T, Masuda K, Kawamoto H, Taniuchi I (2008) Cascading suppression of transcriptional silencers by ThPOK seals helper T cell fate. Nat Immunol 9:1113–1121PubMedCrossRefGoogle Scholar
  74. Naito T, Gomez-Del Arco P, Williams CJ, Georgopoulos K (2007) Antagonistic interactions between Ikaros and the chromatin remodeler Mi-2beta determine silencer activity and Cd4 gene expression. Immunity 27:723–734PubMedCrossRefGoogle Scholar
  75. Naito T, Taniuchi I (2010) The network of transcription factors that underlie the CD4 versus CD8 lineage decision. Int Immunol 22:791–796PubMedCrossRefGoogle Scholar
  76. Ng HH, Robert F, Young RA, Struhl K (2003) Targeted recruitment of Set1 histone methylase by elongating Pol II provides a localized mark and memory of recent transcriptional activity. Mol Cell 11:709–719PubMedCrossRefGoogle Scholar
  77. Ng RK, Gurdon JB (2008) Epigenetic memory of an active gene state depends on histone H3.3 incorporation into chromatin in the absence of transcription. Nat Cell Biol 10:102–109PubMedCrossRefGoogle Scholar
  78. O’Neill MJ (2005) The influence of non-coding RNAs on allele-specific gene expression in mammals. Hum Mol Genet 14 Spec No 1, R113–120Google Scholar
  79. Olins AL, Olins DE (1974) Spheroid chromatin units (v bodies). Science 183:330–332PubMedCrossRefGoogle Scholar
  80. Orphanides G, Reinberg D (2000) RNA polymerase II elongation through chromatin. Nature 407:471–475PubMedCrossRefGoogle Scholar
  81. Osborne CS, Chakalova L, Brown KE, Carter D, Horton A, Debrand E, Goyenechea B, Mitchell JA, Lopes S, Reik W et al (2004) Active genes dynamically colocalize to shared sites of ongoing transcription. Nat Genet 36:1065–1071PubMedCrossRefGoogle Scholar
  82. Ozsolak F, Song JS, Liu XS, Fisher DE (2007) High-throughput mapping of the chromatin structure of human promoters. Nat Biotechnol 25:244–248PubMedCrossRefGoogle Scholar
  83. Pai SY, Truitt ML, Ting CN, Leiden JM, Glimcher LH, Ho IC (2003) Critical roles for transcription factor GATA-3 in thymocyte development. Immunity 19:863–875PubMedCrossRefGoogle Scholar
  84. Petesch SJ, Lis JT (2008) Rapid, transcription-independent loss of nucleosomes over a large chromatin domain at Hsp70 loci. Cell 134:74–84PubMedCrossRefGoogle Scholar
  85. Polansky JK, Kretschmer K, Freyer J, Floess S, Garbe A, Baron U, Olek S, Hamann A, von Boehmer H, Huehn J (2008) DNA methylation controls Foxp3 gene expression. Eur J Immunol 38:1654–1663PubMedCrossRefGoogle Scholar
  86. Reed-Inderbitzin E, Moreno-Miralles I, Vanden-Eynden SK, Xie J, Lutterbach B, Durst-Goodwin KL, Luce KS, Irvin BJ, Cleary ML, Brandt SJ et al (2006) RUNX1 associates with histone deacetylases and SUV39H1 to repress transcription. Oncogene 25:5777–5786PubMedCrossRefGoogle Scholar
  87. Roh TY, Wei G, Farrell CM, Zhao K (2007) Genome-wide prediction of conserved and nonconserved enhancers by histone acetylation patterns. Genome Res 17:74–81PubMedCrossRefGoogle Scholar
  88. Rothenberg EV, Moore JE, Yui MA (2008) Launching the T-cell-lineage developmental programme. Nat Rev Immunol 8:9–21PubMedCrossRefGoogle Scholar
  89. Sado T, Fenner MH, Tan SS, Tam P, Shioda T, Li E (2000) X inactivation in the mouse embryo deficient for Dnmt1: distinct effect of hypomethylation on imprinted and random X inactivation. Dev Biol 225:294–303PubMedCrossRefGoogle Scholar
  90. Sakaguchi S, Hombauer M, Bilic I, Naoe Y, Schebesta A, Taniuchi I, Ellmeier W (2010) The zinc-finger protein MAZR is part of the transcription factor network that controls the CD4 versus CD8 lineage fate of double-positive thymocytes. Nat Immunol 11:442–448PubMedCrossRefGoogle Scholar
  91. Sands JF, Nikolic-Zugic J (1992) T cell-specific protein-DNA interactions occurring at the CD4 locus: identification of possible transcriptional control elements of the murine CD4 gene. Int Immunol 4:1183–1194PubMedCrossRefGoogle Scholar
  92. Sarafova SD, Erman B, Yu Q, Van Laethem F, Guinter T, Sharrow SO, Feigenbaum L, Wildt KF, Ellmeier W, Singer A (2005) Modulation of coreceptor transcription during positive selection dictates lineage fate independently of TCR/coreceptor specificity. Immunity 23:75–87PubMedCrossRefGoogle Scholar
  93. Sato T, Ohno S, Hayashi T, Sato C, Kohu K, Satake M, Habu S (2005) Dual functions of Runx proteins for reactivating CD8 and silencing CD4 at the commitment process into CD8 thymocytes. Immunity 22:317–328PubMedCrossRefGoogle Scholar
  94. Sawada S, Littman DR (1991) Identification and characterization of a T-cell-specific enhancer adjacent to the murine CD4 gene. Mol Cell Biol 11:5506–5515PubMedGoogle Scholar
  95. Sawada S, Littman DR (1993) A heterodimer of HEB and an E12-related protein interacts with the CD4 enhancer and regulates its activity in T-cell lines. Mol Cell Biol 13:5620–5628PubMedGoogle Scholar
  96. Sawada S, Scarborough JD, Killeen N, Littman DR (1994) A lineage-specific transcriptional silencer regulates CD4 gene expression during T lymphocyte development. Cell 77:917–929PubMedCrossRefGoogle Scholar
  97. Singer A, Adoro S, Park JH (2008) Lineage fate and intense debate: myths, models and mechanisms of CD4- versus CD8-lineage choice. Nat Rev Immunol 8:788–801PubMedCrossRefGoogle Scholar
  98. Siu G, Wurster AL, Duncan DD, Soliman TM, Hedrick SM (1994) A transcriptional silencer controls the developmental expression of the CD4 gene. EMBO J 13:3570–3579PubMedGoogle Scholar
  99. Spilianakis CG, Lalioti MD, Town T, Lee GR, Flavell RA (2005) Interchromosomal associations between alternatively expressed loci. Nature 435:637–645PubMedCrossRefGoogle Scholar
  100. Starr TK, Jameson SC, Hogquist KA (2003) Positive and negative selection of T cells. Annu Rev Immunol 21:139–176PubMedCrossRefGoogle Scholar
  101. Sun G, Liu X, Mercado P, Jenkinson SR, Kypriotou M, Feigenbaum L, Galera P, Bosselut R (2005) The zinc finger protein cKrox directs CD4 lineage differentiation during intrathymic T cell positive selection. Nat Immunol 6:373–381PubMedCrossRefGoogle Scholar
  102. Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L et al (2009) Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324:930–935PubMedCrossRefGoogle Scholar
  103. Taniuchi I, Ellmeier W, Littman DR (2004) The CD4/CD8 lineage choice: new insights into epigenetic regulation during T cell development. Adv Immunol 83:55–89PubMedCrossRefGoogle Scholar
  104. Taniuchi I, Osato M, Egawa T, Sunshine MJ, Bae SC, Komori T, Ito Y, Littman DR (2002a) Differential requirements for Runx proteins in CD4 repression and epigenetic silencing during T lymphocyte development. Cell 111:621–633PubMedCrossRefGoogle Scholar
  105. Taniuchi I, Sunshine MJ, Festenstein R, Littman DR (2002b) Evidence for distinct CD4 silencer functions at different stages of thymocyte differentiation. Mol Cell 10:1083–1096PubMedCrossRefGoogle Scholar
  106. Telfer JC, Hedblom EE, Anderson MK, Laurent MN, Rothenberg EV (2004) Localization of the domains in Runx transcription factors required for the repression of CD4 in thymocytes. J Immunol 172:4359–4370PubMedGoogle Scholar
  107. Wan M, Zhang J, Lai D, Jani A, Prestone-Hurlburt P, Zhao L, Ramachandran A, Schnitzler GR, and Chi T (2009) Molecular basis of CD4 repression by the Swi/Snf-like BAF chromatin remodeling complex. Eur J Immunol 39:580–588PubMedCrossRefGoogle Scholar
  108. Wang L, Wildt KF, Castro E, Xiong Y, Feigenbaum L, Tessarollo L, Bosselut R (2008a) The zinc finger transcription factor Zbtb7b represses CD8-lineage gene expression in peripheral CD4+ T cells. Immunity 29:876–887PubMedCrossRefGoogle Scholar
  109. Wang L, Wildt KF, Zhu J, Zhang X, Feigenbaum L, Tessarollo L, Paul WE, Fowlkes BJ, Bosselut R (2008b) Distinct functions for the transcription factors GATA-3 and ThPOK during intrathymic differentiation of CD4(+) T cells. Nat Immunol 9:1122–1130PubMedCrossRefGoogle Scholar
  110. Williams LM, Rudensky AY (2007) Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat Immunol 8:277–284PubMedCrossRefGoogle Scholar
  111. Woodcock CL, Ghosh RP (2010) Chromatin higher-order structure and dynamics. Cold Spring Harb Perspect Biol 2:a000596PubMedCrossRefGoogle Scholar
  112. Wu C, Wong YC, Elgin SC (1979) The chromatin structure of specific genes: II. Disruption of chromatin structure during gene activity. Cell 16:807–814Google Scholar
  113. Wu H, Coskun V, Tao J, Xie W, Ge W, Yoshikawa K, Li E, Zhang Y, Sun YE (2010) Dnmt3a-dependent nonpromoter DNA methylation facilitates transcription of neurogenic genes. Science 329:444–448PubMedCrossRefGoogle Scholar
  114. Wurster AL, Siu G, Leiden JM, Hedrick SM (1994) Elf-1 binds to a critical element in a second CD4 enhancer. Mol Cell Biol 14:6452–6463PubMedGoogle Scholar
  115. Wutz A, Jaenisch R (2000) A shift from reversible to irreversible X inactivation is triggered during ES cell differentiation. Mol Cell 5:695–705PubMedCrossRefGoogle Scholar
  116. Yarmus M, Woolf E, Bernstein Y, Fainaru O, Negreanu V, Levanon D, Groner Y (2006) Groucho/transducin-like enhancer-of-split (TLE)-dependent and -independent transcriptional regulation by Runx3. Proc Natl Acad Sci U S A 103:7384–7389PubMedCrossRefGoogle Scholar
  117. Yu M, Wan M, Zhang J, Wu J, Khatri R, Chi T (2008) Nucleoprotein structure of the CD4 locus: implications for the mechanisms underlying CD4 regulation during T cell development. Proc Natl Acad Sci U S A 105:3873–3878PubMedCrossRefGoogle Scholar
  118. Zhang XL, Seong R, Piracha R, Larijani M, Heeney M, Parnes JR, Chamberlain JW (1998) Distinct stage-specific cis-active transcriptional mechanisms control expression of T cell coreceptor CD8 alpha at double- and single-positive stages of thymic development. J Immunol 161:2254–2266PubMedGoogle Scholar
  119. Zhang XL, Zhao S, Borenstein SH, Liu Y, Jayabalasingham B, Chamberlain JW (2001) CD8 expression up to the double-positive CD3(low/intermediate) stage of thymic differentiation is sufficient for development of peripheral functional cytotoxic T lymphocytes. J Exp Med 194:685–693PubMedCrossRefGoogle Scholar
  120. Zheng Y, Josefowicz S, Chaudhry A, Peng XP, Forbush K, Rudensky AY (2010) Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 463:808–812PubMedCrossRefGoogle Scholar
  121. Zou YR, Sunshine MJ, Taniuchi I, Hatam F, Killeen N, Littman DR (2001) Epigenetic silencing of CD4 in T cells committed to the cytotoxic lineage. Nat Genet 29:332–336PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2011

Authors and Affiliations

  • Manolis Gialitakis
    • 1
  • MacLean Sellars
    • 1
  • Dan R. Littman
    • 1
    Email author
  1. 1.Molecular Pathogenesis Program, Howard Hughes Medical Institute, Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine New York University School of MedicineNew YorkUSA

Personalised recommendations