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:

Genome-scale profiling reveals a subset of genes regulated by DNA methylation that program somatic T-cell phenotypes in humans

Abstract

The aim of this study was to investigate the dynamics and relationship between DNA methylation and gene expression during early T-cell development. Mononuclear cells were collected at birth and at 12 months from 60 infants and were either activated with anti-CD3 for 24 h or cultured in media alone, and the CD4+ T-cell subset purified. DNA and RNA were co-harvested and DNA methylation was measured in 450 000 CpG sites in parallel with expression measurements taken from 25 000 genes. In unstimulated cells, we found that a subset of 1188 differentially methylated loci were associated with a change in expression in 599 genes (adjusted P value<0.01, β-fold >0.1). These genes were enriched in reprogramming regions of the genome known to control pluripotency. In contrast, over 630 genes were induced following low-level T-cell activation, but this was not associated with any significant change in DNA methylation. We conclude that DNA methylation is dynamic during early T-cell development, and has a role in the consolidation of T-cell-specific gene expression. During the early phase of clonal expansion, DNA methylation is stable and therefore appears to be of limited importance in short-term T-cell responsiveness.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

Accession codes

Accessions

Gene Expression Omnibus

References

  1. Fink PJ, Hendricks DW . Post-thymic maturation: young T cells assert their individuality. Nat Rev Immunol 2011; 11: 544–549.

    Article  CAS  PubMed Central  Google Scholar 

  2. Zaghouani H, Hoeman CM, Adkins B . Neonatal immunity: faulty T-helpers and the shortcomings of dendritic cells. Trends Immunol 2009; 30: 585–591.

    Article  CAS  PubMed Central  Google Scholar 

  3. Williams M, Georas S . Gene expression patterns and susceptibility to allergic responses. Expert Rev Clin Immunol 2006; 2: 59–73.

    Article  Google Scholar 

  4. Vuillermin PJ, Ponsonby AL, Saffery R, Tang ML, Ellis JA, Sly P et al. Microbial exposure, interferon gamma gene demethylation in naïve T-cells, and the risk of allergic disease. Allergy 2009; 64: 348–353.

    Article  CAS  Google Scholar 

  5. Zhou L, Chong MMW, Littman DR . Plasticity of CD4(+) T cell lineage differentiation. Immunity 2009; 30: 646–655.

    Article  CAS  Google Scholar 

  6. Wilson CB, Rowell E, Sekimata M . Epigenetic control of T-helper-cell differentiation. Nat Rev Immunol 2009; 9: 91–105.

    Article  CAS  PubMed Central  Google Scholar 

  7. Murphy KM, Stockinger B . Effector T cell plasticity: flexibility in the face of changing circumstances. Nat Immunol 2010; 11: 674–680.

    Article  CAS  PubMed Central  Google Scholar 

  8. Cuddapah S, Barski A, Zhao K . Epigenomics of T cell activation, differentiation, and memory. Curr Opin Immunol 2010; 22: 341–347.

    Article  CAS  PubMed Central  Google Scholar 

  9. Cohen CJ, Crome SQ, MacDonald KG, Dai EL, Mager DL, Levings MK . Human Th1 and th17 cells exhibit epigenetic stability at signature cytokine and transcription factor Loci. J Immunol 2011; 187: 5615–5626.

    Article  CAS  Google Scholar 

  10. Beyer M, Thabet Y, Müller RU, Sadlon T, Classen S, Lahl K et al. Repression of the genome organizer SATB1 in regulatory T cells is required for suppressive function and inhibition of effector differentiation. Nat Immunol 2011; 12: 898–907.

    Article  CAS  PubMed Central  Google Scholar 

  11. Floess S, Freyer J, Siewert C, Baron U, Olek S, Polansky J et al. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol 2007; 5: e38.

    Article  PubMed Central  Google Scholar 

  12. Janson PCJ, Winerdal ME, Winqvist O . At the crossroads of T helper lineage commitment-Epigenetics points the way. Bba-Gen Subjects 2009; 1790: 906–919.

    Article  CAS  Google Scholar 

  13. Yamashita M, Ukai-Tadenuma M, Miyamoto T, Sugaya K, Hosokawa H, Hasegawa A et al. Essential role of GATA3 for the maintenance of type 2 helper T (Th2) cytokine production and chromatin remodeling at the Th2 cytokine gene loci. J Biol Chem 2004; 279: 26983–26990.

    Article  CAS  Google Scholar 

  14. O'Shea JJ, Paul WE . Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 2010; 327: 1098–1102.

    Article  CAS  PubMed Central  Google Scholar 

  15. Lee D, Agarwal S, Rao A . Th2 lineage commitment and efficient IL-4 production involves extended demethylation of the IL-4 gene. Immunity 2002; 16: 649–660.

    Article  CAS  Google Scholar 

  16. YOUNG H, Ghosh P, Ye J, Lederer J, Lichtman A, Gerard JR et al. Differentiation of the T-Helper phenotypes by analysis of the methylation state of the ifn-gamma gene. J Immunol 1994; 153: 3603–3610.

    CAS  PubMed  Google Scholar 

  17. Fields P, Lee G, Kim S, Bartsevich V, Flavell R . Th2-specific chromatin remodeling and enhancer activity in the Th2 cytokine locus control region. Immunity 2005; 21: 865–876.

    Article  Google Scholar 

  18. White GP, Hollams EM, Yerkovich ST, Bosco A, Holt BJ, Bassami MR et al. CpG methylation patterns in the IFN gamma; promoter in naive T cells: Variations during Th1 and Th2 differentiation and between atopics and non-atopics. Pediatr Allergy Immunol 2006; 17: 557–564.

    Article  Google Scholar 

  19. Dreyer W . The area code hypothesis revisited: olfactory receptors and other related transmembrane receptors may function as the last digits in a cell surface code for assembling embryos. Proc Natl Acad Sci USA 1998; 95: 9072–9077.

    Article  CAS  Google Scholar 

  20. Strous RD, Shoenfeld Y . To smell the immune system: olfaction, autoimmunity and brain involvement. Autoimmun Rev 2006; 6: 54–60.

    Article  CAS  Google Scholar 

  21. Irizarry RA, Ladd-Acosta C, Wen B, Wu Z, Montano C, Onyango P et al. The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet 2009; 41: 178–186.

    Article  CAS  PubMed Central  Google Scholar 

  22. Hendricks DW, Fink PJ . Recent thymic emigrants are biased against the T-helper type 1 and toward the T-helper type 2 effector lineage. Blood 2011; 117: 1239–1249.

    Article  CAS  PubMed Central  Google Scholar 

  23. Haines CJ, Giffon TD, Lu LS, Lu X, Tessier-Lavigne M, Ross DT et al. Human CD4+ T cell recent thymic emigrants are identified by protein tyrosine kinase 7 and have reduced immune function. J Exp Med 2009; 206: 275–285.

    Article  CAS  PubMed Central  Google Scholar 

  24. Mold JE, McCune JM . At the crossroads between tolerance and aggression: revisiting the ‘layered immune system’ hypothesis. Chimerism 2011; 2: 35–41.

    Article  PubMed Central  Google Scholar 

  25. Boursalian T, Golob J, Soper D, Cooper C, Fink P . Continued maturation of thymic emigrants in the periphery. Nat Immunol 2004; 5: 418–425.

    Article  CAS  Google Scholar 

  26. Martino D, Prescott S . Epigenetics and prenatal influences on asthma and allergic airways disease. Chest 2011; 139: 640–647.

    Article  CAS  Google Scholar 

  27. Kuriakose JS, Miller RL . Environmental epigenetics and allergic diseases: recent advances. Clin Exp Allergy 2010; 40: 1602–1610.

    Article  CAS  PubMed Central  Google Scholar 

  28. Hughes T, Webb R, Fei Y, Wren JD, Sawalha AH . DNA methylome in human CD4+ T cells identifies transcriptionally repressive and non-repressive methylation peaks. Genes Immun 2010; 11: 554–560.

    Article  CAS  PubMed Central  Google Scholar 

  29. Doi A, Park IH, Wen B, Murakami P, Aryee MJ, Irizarry R et al. Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts. Nat Genet 2009; 41: 1350–1353.

    Article  CAS  PubMed Central  Google Scholar 

  30. Thornton CA, Upham JW, Wikström ME, Holt BJ, White GP, Sharp MJ et al. Functional maturation of CD4+CD25+CTLA4+CD45RA+ T regulatory cells in human neonatal T cell responses to environmental antigens/allergens. J Immun 2004; 173: 3084–3092.

    Article  CAS  Google Scholar 

  31. Gavin MA, Bevan MJ . Increased peptide promiscuity provides a rationale for the lack of N regions in the neonatal T cell repertoire. Immunity 1995; 3: 793–800.

    Article  CAS  Google Scholar 

  32. Li Y, Kurlander RJ . Comparison of anti-CD3 and anti-CD28-coated beads with soluble anti-CD3 for expanding human T cells: differing impact on CD8 T cell phenotype and responsiveness to restimulation. J Transl Med 2010; 8: 104.

    Article  PubMed Central  Google Scholar 

  33. Dubey C, Croft M, SWAIN S . Costimulatory requirements of naive Cd4(+) T-cells—Icam-1 or B7-1 Can costimulate naive cd4 t-cell activation but both are required for optimum response. J Immunol 1995; 155: 45–57.

    CAS  PubMed  Google Scholar 

  34. Croft M, Bradley L, SWAIN S . Naive versus memory Cd4 T-cell response to antigen—memory cells are less dependent on accessory cell costimulation and can respond to many antigen-presenting cell-types including resting B-cells. J Immunol 1994; 152: 2675–2685.

    CAS  PubMed  Google Scholar 

  35. Kuromitsu J, Kataoka H, Yamashita H, Muramatsu M, Furuichi Y, Sekine T et al. Reproducible alterations of DNA methylation at a specific population of CpG islands during blast formation of peripheral blood lymphocytes. DNA Res 1995; 2: 263–267.

    Article  CAS  Google Scholar 

  36. Docherty SJ, Davis OSP, Haworth CMA, Plomin R, Mill J . Bisulfite-based epityping on pooled genomic DNA provides an accurate estimate of average group DNA methylation. Epigenet Chromatin 2009; 2: 3.

    Article  Google Scholar 

  37. Prescott SL, Macaubas C, Holt BJ, Smallacombe TB, Loh R, Sly PD et al. Transplacental priming of the human immune system to environmental allergens: universal skewing of initial t cell responses toward the Th2 cytokine profile. J Immunol 1998; 160: 4730–4737.

    CAS  PubMed  Google Scholar 

  38. Fleischer J, Soeth E, Reiling N, Grage-Griebenow E, Flad HD, Ernst M . Differential expression and function of CD8O (B7-1) and CD86 (B7-2) on human peripheral blood monocytes. Immunology 1996; 89: 592–598.

    Article  CAS  PubMed Central  Google Scholar 

  39. Warnes GR . gplots: various R programming tools for plotting data 2010. http://cran.r-project.org/web/packages/gplots/index.html.

  40. Davis S, Du P, Bilke S, Trich Jr T, Bootwalla M methylumi: handle Illumina methylation data. http://www.bioconductor.org/packages/release/bioc/html/methylumi.html.

  41. Martino DJ, Bosco A, McKenna KL, Hollams E, Mok D, Holt PG et al. T-cell activation genes differentially expressed at birth in CD4(+) T-cells from children who develop IgE food allergy. Allergy 2012; 67: 191–200.

    Article  CAS  Google Scholar 

  42. Du P, Kibbe WA, Lin SM . lumi: a pipeline for processing Illumina microarray. Bioinformatics 2008; 24: 1547–1548.

    Article  CAS  Google Scholar 

  43. Benjamini Y, Hochberg Y . Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Statist Soc 1995; 57: 289–300.

    Google Scholar 

  44. Efron B, Tibshirani R . On testing the significance of sets of genes. Ann Appl Stat 2007; 1: 107–129.

    Article  Google Scholar 

  45. Huang DW, Sherman BT, Lempicki RA . Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 2009; 4: 44–57.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We wish to thank Dr Alicia Oshlack and Dr Lavinia Gordon for advice on data analysis.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to R Saffery.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on Genes and Immunity website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Martino, D., Maksimovic, J., Joo, JH. et al. Genome-scale profiling reveals a subset of genes regulated by DNA methylation that program somatic T-cell phenotypes in humans. Genes Immun 13, 388–398 (2012). https://doi.org/10.1038/gene.2012.7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gene.2012.7

Keywords

This article is cited by

Search

Quick links