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:

Lineage-specific adjacent IFNG and IL26 genes share a common distal enhancer element

Genes & Immunity volume 13, pages 481–488 (2012)Cite this article

Subjects

Abstract

Certain groups of physically linked genes remain linked over long periods of evolutionary time. The general view is that such evolutionary conservation confers ‘fitness’ to the species. Why gene order confers ‘fitness’ to the species is incompletely understood. For example, linkage of IL26 and IFNG is preserved over evolutionary time yet Th17 lineages express IL26 and Th1 lineages express IFNG. We considered the hypothesis that distal enhancer elements may be shared between adjacent genes, which would require linkage be maintained in evolution. We test this hypothesis using a bacterial artificial chromosome transgenic model with deletions of specific conserved non-coding sequences. We identify one enhancer element uniquely required for IL26 expression but not for IFNG expression. We identify a second enhancer element positioned between IL26 and IFNG required for both IL26 and IFNG expression. One function of this enhancer is to facilitate recruitment of RNA polymerase II to promoters of both genes. Thus, sharing of distal enhancers between adjacent genes may contribute to evolutionary preservation of gene order.

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
Figure 7

Similar content being viewed by others

References

  1. Boniface K, Blumenschein WM, Brovont-Porth K, McGeachy MJ, Basham B, Desai B et al. Human Th17 cells comprise heterogeneous subsets including IFN-gamma-producing cells with distinct properties from the Th1 lineage. J Immunol 2010; 185: 679–687.

    Article  CAS  Google Scholar 

  2. Cella M, Fuchs A, Vermi W, Facchetti F, Otero K, Lennerz JK et al. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature 2009; 457: 722–725.

    Article  CAS  Google Scholar 

  3. Chang SH, Dong C . Signaling of interleukin-17 family cytokines in immunity and inflammation. Cell Signal 2011; 23: 1069–1075.

    Article  CAS  Google Scholar 

  4. Commins S, Steinke JW, Borish L . The extended IL-10 superfamily: IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, and IL-29. J Allergy Clin Immunol 2008; 121: 1108–1111.

    Article  CAS  Google Scholar 

  5. Korn T, Bettelli E, Oukka M, Kuchroo VK . IL-17 and Th17 cells. Annu Rev Immunol 2009; 27: 485–517.

    Article  CAS  Google Scholar 

  6. Lohr J, Knoechel B, Caretto D, Abbas AK . Balance of Th1 and Th17 effector and peripheral regulatory T cells. Microbes Infect 2009; 11: 589–593.

    Article  CAS  Google Scholar 

  7. Manel N, Unutmaz D, Littman DR . The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat Immunol 2008; 9: 641–649.

    Article  CAS  Google Scholar 

  8. Pene J, Chevalier S, Preisser L, Venereau E, Guilleux MH, Ghannam S et al. Chronically inflamed human tissues are infiltrated by highly differentiated Th17 lymphocytes. J Immunol 2008; 180: 7423–7430.

    Article  CAS  Google Scholar 

  9. Romagnani S, Maggi E, Liotta F, Cosmi L, Annunziato F . Properties and origin of human Th17 cells. Mol Immunol 2009; 47: 3–7.

    Article  CAS  Google Scholar 

  10. Reiner SL . Development in motion: helper T cells at work. Cell 2007; 129: 33–36.

    Article  CAS  Google Scholar 

  11. Weaver CT, Hatton RD, Mangan PR, Harrington LE . IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol 2007; 25: 821–852.

    Article  CAS  Google Scholar 

  12. Wilson NJ, Boniface K, Chan JR, McKenzie BS, Blumenschein WM, Mattson JD et al. Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol 2007; 8: 950–957.

    Article  CAS  Google Scholar 

  13. Zhou L, Chong MM, Littman DR . Plasticity of CD4+ T cell lineage differentiation. Immunity 2009; 30: 646–655.

    Article  CAS  Google Scholar 

  14. Zhu J, Paul WE . Peripheral CD4+ T-cell differentiation regulated by networks of cytokines and transcription factors. Immunol Rev 2010; 238: 247–262.

    Article  CAS  Google Scholar 

  15. Zhu J, Paul WE . Heterogeneity and plasticity of T helper cells. Cell Res 2010; 20: 4–12.

    Article  Google Scholar 

  16. Zhu J, Yamane H, Paul WE . Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol 2010; 28: 445–489.

    Article  CAS  Google Scholar 

  17. Lee GR, Fields PE, Griffin TJ, Flavell RA . Regulation of the Th2 cytokine locus by a locus control region. Immunity 2003; 19: 145–153.

    Article  CAS  Google Scholar 

  18. Lutfalla G, Roest Crollius H, Stange-Thomann N, Jaillon O, Mogensen K, Monneron D . Comparative genomic analysis reveals independent expansion of a lineage-specific gene family in vertebrates: the class II cytokine receptors and their ligands in mammals and fish. BMC Genomics 2003; 4: 29.

    Article  Google Scholar 

  19. Igawa D, Sakai M, Savan R . An unexpected discovery of two interferon gamma-like genes along with interleukin (IL)-22 and -26 from teleost: IL-22 and -26 genes have been described for the first time outside mammals. Mol Immunol 2006; 43: 999–1009.

    Article  CAS  Google Scholar 

  20. Qi ZT, Nie P . Comparative study and expression analysis of the interferon gamma gene locus cytokines in Xenopus tropicalis. Immunogenetics 2008; 60: 699–710.

    Article  CAS  Google Scholar 

  21. International Chicken Genome Sequencing Consortium. Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution. Nature 2004; 432: 695–716.

  22. Dumoutier L, Van Roost E, Ameye G, Michaux L, Renauld JC . IL-TIF/IL-22: genomic organization and mapping of the human and mouse genes. Genes Immun 2000; 1: 488–494.

    Article  CAS  Google Scholar 

  23. Sheikh F, Baurin VV, Lewis-Antes A, Shah NK, Smirnov SV, Anantha S et al. Cutting edge: IL-26 signals through a novel receptor complex composed of IL-20 receptor 1 and IL-10 receptor 2. J Immunol 2004; 172: 2006–2010.

    Article  CAS  Google Scholar 

  24. Cavalier-Smith T . Evolution of the eukaryotic genome. In: Broda P, Oliver S, Sims P (eds) The Eukaryotic Genome: Organization and Regulation. Cambridge University Press: Cambridge, 1993, pp 333–385.

    Google Scholar 

  25. Maynard-Smith J . Evolutionary Genetics 2nd edn Oxford University Press: Oxford, 1998.

    Google Scholar 

  26. Lercher MJ, Urrutia AO, Hurst LD . Clustering of housekeeping genes provides a unified model of gene order in the human genome. Nat Genet 2002; 31: 180–183.

    Article  CAS  Google Scholar 

  27. Lercher MJ, Urrutia AO, Pavlicek A, Hurst LD . A unification of mosaic structures in the human genome. Hum Mol Genet 2003; 12: 2411–2415.

    Article  CAS  Google Scholar 

  28. Versteeg R, van Schaik BD, van Batenburg MF, Roos M, Monajemi R, Caron H et al. The human transcriptome map reveals extremes in gene density, intron length, GC content, and repeat pattern for domains of highly and weakly expressed genes. Genome Res 2003; 13: 1998–2004.

    Article  CAS  Google Scholar 

  29. Hurst LD, Pal C, Lercher MJ . The evolutionary dynamics of eukaryotic gene order. Nat Rev Genet 2004; 5: 299–310.

    Article  CAS  Google Scholar 

  30. Poyatos JF, Hurst LD . The determinants of gene order conservation in yeasts. Genome Biol 2007; 8: R233.

    Article  Google Scholar 

  31. Hurst LD . Fundamental concepts in genetics: genetics and the understanding of selection. Nat Rev Genet 2009; 10: 83–93.

    Article  CAS  Google Scholar 

  32. Zhou W, Chang S, Aune TM . Long-range histone acetylation of the Ifng gene is an essential feature of T cell differentiation. Proc Natl Acad Sci USA 2004; 101: 2440–2445.

    Article  CAS  Google Scholar 

  33. Chang S, Aune TM . Histone hyperacetylated domains across the Ifng gene region in natural killer cells and T cells. Proc Natl Acad Sci USA 2005; 102: 17095–17100.

    Article  CAS  Google Scholar 

  34. Aune TM, Collins PL, S Chang . Epigenetics and T helper 1 differentiation. Immunology 2009; 126: 299–305.

    Article  CAS  Google Scholar 

  35. Schoenborn JR, Dorschner MO, Sekimata M, Santer DM, Shnyreva M, Fitzpatrick DR et al. Comprehensive epigenetic profiling identifies multiple distal regulatory elements directing transcription of the gene encoding interferon-gamma. Nat Immunol 2007; 8: 732–742.

    Article  CAS  Google Scholar 

  36. Maston GA, Evans SK, Green MR . Transcriptional regulatory elements in the human genome. Annu Rev Genomics Hum Genet 2006; 7: 29–59.

    Article  CAS  Google Scholar 

  37. Visel A, Rubin EM, Pennacchio LA . Genomic views of distant-acting enhancers. Nature 2009; 461: 199–205.

    Article  CAS  Google Scholar 

  38. Visel A, Akiyama JA, Shoukry M, Afzal V, Rubin EM, Pennacchio LA . Functional autonomy of distant-acting human enhancers. Genomics 2009; 93: 509–513.

    Article  CAS  Google Scholar 

  39. Visel A, Blow MJ, Li Z, Zhang T, Akiyama JA, Holt A et al. ChIP-seq accurately predicts tissue-specific activity of enhancers. Nature 2009; 457: 854–858.

    Article  CAS  Google Scholar 

  40. Heintzman ND, Hon GC, Hawkins RD, Kheradpour P, Stark A, Harp LF et al. Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature 2009; 459: 108–112.

    Article  CAS  Google Scholar 

  41. Collins PL, Chang S, Henderson M, Soutto M, Davis GM, McLoed AG et al. Distal regions of the human IFNG locus direct cell type-specific expression. J Immunol 2010; 185: 1492–1501.

    Article  CAS  Google Scholar 

  42. Collins PL, Henderson MA, Aune TM . Diverse functions of distal regulatory elements at the IFNG locus. J Immunol 2012; 188: 1726–1733.

    Article  CAS  Google Scholar 

  43. Ernst J, Kheradpour P, Mikkelsen TS, Shoresh N, Ward LD, Epstein CB et al. Mapping and analysis of chromatin state dynamics in nine human cell types. Nature 2011; 473: 43–49.

    Article  CAS  Google Scholar 

  44. Rosenbloom KR, Dreszer TR, Long JC, Malladi VS, Sloan CA, Raney BJ et al. ENCODE whole-genome data in the UCSC Genome Browser: update 2012. Nucleic Acids Res 2012; 40 (Database issue): D912–D917.

    Article  CAS  Google Scholar 

  45. Kong S, Bohl D, Li C, Tuan D . Transcription of the HS2 enhancer toward a cis-linked gene is independent of the orientation, position, and distance of the enhancer relative to the gene. Mol Cell Biol 1997; 17: 3955–3965.

    Article  CAS  Google Scholar 

  46. Gillies SD, Morrison SL, Oi VT, Tonegawa S . A tissue-specific transcription enhancer element is located in the major intron of a rearranged immunoglobulin heavy chain gene. Cell 1983; 33: 717–728.

    Article  CAS  Google Scholar 

  47. Banerji J, Olson L, Schaffner W . A lymphocyte-specific cellular enhancer is located downstream of the joining region in immunoglobulin heavy chain genes. Cell 1983; 33: 729–740.

    Article  CAS  Google Scholar 

  48. Banerji J, Rusconi S, Schaffner W . Expression of a beta-globin gene is enhanced by remote SV40 DNA sequences. Cell 1981; 27 (Pt 1): 299–308.

    Article  CAS  Google Scholar 

  49. Ciccarone VC, Chrivia J, Hardy KJ, Young HA . Identification of enhancer-like elements in human IFN-gamma genomic DNA. J Immunol 1990; 144: 725–730.

    CAS  PubMed  Google Scholar 

  50. Gonsky R, Deem RL, Bream JH, Lee DH, Young HA, Targan SR . Mucosa-specific targets for regulation of IFN-gamma expression: lamina propria T cells use different cis-elements than peripheral blood T cells to regulate transactivation of IFN-gamma expression. J Immunol 2000; 164: 1399–1407.

    Article  CAS  Google Scholar 

  51. Hadjur S, Williams LM, Ryan NK, Cobb BS, Sexton T, Fraser P et al. Cohesins form chromosomal cis-interactions at the developmentally regulated IFNG locus. Nature 2009; 460: 410–413.

    Article  CAS  Google Scholar 

  52. Sekimata M, Perez-Melgosa M, Miller SA, Weinmann AS, Sabo PJ, Sandstrom R et al. CCCTC-binding factor and the transcription factor T-bet orchestrate T helper 1 cell-specific structure and function at the interferon-gamma locus. Immunity 2009; 31: 551–564.

    Article  CAS  Google Scholar 

  53. Eyerich S, Eyerich K, Pennino D, Carbone T, Nasorri F, Pallotta S et al. Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling. J Clin Invest 2009; 119: 3573–3585.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Zielinski CE, Mele F, Aschenbrenner D, Jarrossay D, Ronchi F, Gattorno M et al. Pathogen-induced human TH17 cells produce IFN-γ or IL-10 and are regulated by IL-1β. Nature 2012; 484: 514–518.

    Article  CAS  Google Scholar 

  55. Geremia A, Arancibia-Carcamo CV, Fleming MP, Rust N, Singh B, Mortensen NJ et al. IL-23-responsive innate lymphoid cells are increased in inflammatory bowel disease. J Exp Med 2011; 208: 1127–1133.

    Article  CAS  Google Scholar 

  56. Eskiw CH, Cope NF, Clay I, Schoenfelder S, Nagano T, Fraser P . Transcription factories and nuclear organization of the genome. Cold Spring Harb Symp Quant Biol 2010; 75: 501–506.

    Article  CAS  Google Scholar 

  57. Osborne CS, Chakalova L, Brown KE, Carter D, Horton A, Debrand E et al. Active genes dynamically colocalize to shared sites of ongoing transcription. Nat Genet 2004; 36: 1065–1071.

    Article  CAS  Google Scholar 

  58. Spilianakis CG, Lalioti MD, Town T, Lee GR, Flavell RA . Interchromosomal associations between alternatively expressed loci. Nature 2005; 435: 637–645.

    Article  CAS  Google Scholar 

  59. Eivazova ER, Aune TM . Dynamic alterations in the conformation of the Ifng gene region during T helper cell differentiation. Proc Natl Acad Sci USA 2004; 101: 251–256.

    Article  CAS  Google Scholar 

  60. Dekker J, Rippe K, Dekker M, Kleckner N . Capturing chromosome conformation. Science 2002; 295: 1306–1311.

    Article  CAS  Google Scholar 

  61. Voss TC, Schiltz RL, Sung MH, Yen PM, Stamatoyannopoulos JA, Biddie SC et al. Dynamic exchange at regulatory elements during chromatin remodeling underlies assisted loading mechanism. Cell 2011; 146: 544–554.

    Article  CAS  Google Scholar 

  62. Hakim O, Sung MH, Voss TC, Splinter E, John S, Sabo PJ et al. Diverse gene reprogramming events occur in the same spatial clusters of distal regulatory elements. Genome Res 2011; 21: 697–706.

    Article  CAS  Google Scholar 

  63. Waterston RH, Lindblad-Toh K, Birney E, Rogers J, Abril JF, Agarwal P et al. Initial sequencing and comparative analysis of the mouse genome. Nature 2002; 420: 520–562.

    Article  CAS  Google Scholar 

  64. Pevzner P, Tesler G . Human and mouse genomic sequences reveal extensive breakpoint reuse in mammalian evolution. Proc Natl Acad Sci USA 2003; 100: 7672–7677.

    Article  CAS  Google Scholar 

  65. Kleinjan DA, Bancewicz RM, Gautier P, Dahm R, Schonthaler HB, Damante G et al. Subfunctionalization of duplicated zebrafish pax6 genes by cis-regulatory divergence. PLoS Genet 2008; 4: e29.

    Article  Google Scholar 

  66. Reed NP, Mortlock DP . Identification of a distant cis-regulatory element controlling pharyngeal arch-specific expression of zebrafish gdf6a/radar. Dev Dyn 2010; 239: 1047–1060.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the National Institutes of Health (RO1 AI44924 and training grant (T32 HL069765). The Vanderbilt Transgenic/Embryonic Stem Cell Shared Resource is supported in part by the NIH grant CA68485.

Author contributions: TMA and PLC conceived and designed the project. PLC and MAH prepared BAC constructs with deletions for transgenesis and maintained the mouse colony. PLC performed experiments. TMA and PLC wrote the manuscript with input from MAH.

Author information

Authors and Affiliations

  1. Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA

    P L Collins & T M Aune

  2. Department of Medicine, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    P L Collins, M A Henderson & T M Aune

Authors
  1. P L Collins
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M A Henderson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T M Aune
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T M Aune.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Collins, P., Henderson, M. & Aune, T. Lineage-specific adjacent IFNG and IL26 genes share a common distal enhancer element. Genes Immun 13, 481–488 (2012). https://doi.org/10.1038/gene.2012.22

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gene.2012.22

Keywords

This article is cited by

Search

Advanced search

Quick links