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An epigenetic silencing pathway controlling T helper 2 cell lineage commitment

Nature volume 487, pages 249–253 (2012)Cite this article

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Abstract

During immune responses, naive CD4+ T cells differentiate into several T helper (TH) cell subsets under the control of lineage-specifying genes. These subsets (TH1, TH2 and TH17 cells and regulatory T cells) secrete distinct cytokines and are involved in protection against different types of infection. Epigenetic mechanisms are involved in the regulation of these developmental programs, and correlations have been drawn between the levels of particular epigenetic marks and the activity or silencing of specifying genes during differentiation1,2,3. Nevertheless, the functional relevance of the epigenetic pathways involved in TH cell subset differentiation and commitment is still unclear. Here we explore the role of the SUV39H1–H3K9me3–HP1α silencing pathway in the control of TH2 lineage stability. This pathway involves the histone methylase SUV39H1, which participates in the trimethylation of histone H3 on lysine 9 (H3K9me3), a modification that provides binding sites for heterochromatin protein 1α (HP1α)4,5 and promotes transcriptional silencing. This pathway was initially associated with heterochromatin formation and maintenance6 but can also contribute to the regulation of euchromatic genes7,8,9. We now propose that the SUV39H1–H3K9me3–HP1α pathway participates in maintaining the silencing of TH1 loci, ensuring TH2 lineage stability. In TH2 cells that are deficient in SUV39H1, the ratio between trimethylated and acetylated H3K9 is impaired, and the binding of HP1α at the promoters of silenced TH1 genes is reduced. Despite showing normal differentiation, both SUV39H1-deficient TH2 cells and HP1α-deficient TH2 cells, in contrast to wild-type cells, expressed TH1 genes when recultured under conditions that drive differentiation into TH1 cells. In a mouse model of TH2-driven allergic asthma, the chemical inhibition or loss of SUV39H1 skewed T-cell responses towards TH1 responses and decreased the lung pathology. These results establish a link between the SUV39H1–H3K9me3–HP1α pathway and the stability of TH2 cells, and they identify potential targets for therapeutic intervention in TH2-cell-mediated inflammatory diseases.

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Figure 1: H3K9me3 and H3K9ac mark the promoters of silenced and active T H lineage genes, respectively.
Figure 2: SUV39H1 deficiency results in increased plasticity of T H 2 cells under T H 1-promoting conditions and correlates with an impaired ratio of H3K9 modifications in T H 1 gene promoters.
Figure 3: HP1α participates in T H 1 gene silencing in T H 2 cells in an SUV39H1-dependent manner.
Figure 4: SUV39H1 deficiency impairs T H 2 stability in vivo and reduces allergic lung inflammation.

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References

  1. Avni, O. et al. TH cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes. Nature Immunol. 3, 643–651 (2002)

    Article  CAS  Google Scholar 

  2. Wei, G. et al. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 30, 155–167 (2009)

    Article  PubMed  PubMed Central  Google Scholar 

  3. Chang, S. & Aune, T. M. Dynamic changes in histone-methylation ‘marks’ across the locus encoding interferon-γ during the differentiation of T helper type 2 cells. Nature Immunol. 8, 723–731 (2007)

    Article  CAS  Google Scholar 

  4. Lachner, M., O’Carroll, D., Rea, S., Mechtler, K. & Jenuwein, T. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 410, 116–120 (2001)

    Article  ADS  CAS  PubMed  Google Scholar 

  5. Bannister, A. J. et al. Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature 410, 120–124 (2001)

    Article  ADS  CAS  PubMed  Google Scholar 

  6. Maison, C. & Almouzni, G. HP1 and the dynamics of heterochromatin maintenance. Nature Rev. Mol. Cell Biol. 5, 296–305 (2004)

    Article  CAS  Google Scholar 

  7. Nielsen, S. J. et al. Rb targets histone H3 methylation and HP1 to promoters. Nature 412, 561–565 (2001)

    Article  ADS  CAS  PubMed  Google Scholar 

  8. Wiencke, J. K., Zheng, S., Morrison, Z. & Yeh, R. F. Differentially expressed genes are marked by histone 3 lysine 9 trimethylation in human cancer cells. Oncogene 27, 2412–2421 (2008)

    Article  CAS  PubMed  Google Scholar 

  9. Ait-Si-Ali, S. et al. A Suv39h-dependent mechanism for silencing S-phase genes in differentiating but not in cycling cells. EMBO J. 23, 605–615 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wilson, C. B., Rowell, E. & Sekimata, M. Epigenetic control of T-helper-cell differentiation. Nature Rev. Immunol. 9, 91–105 (2009)

    Article  CAS  Google Scholar 

  11. Peters, A. H. et al. Loss of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome stability. Cell 107, 323–337 (2001)

    Article  CAS  PubMed  Google Scholar 

  12. Grogan, J. L. et al. Early transcription and silencing of cytokine genes underlie polarization of T helper cell subsets. Immunity 14, 205–215 (2001)

    Article  CAS  PubMed  Google Scholar 

  13. Wang, H. et al. mAM facilitates conversion by ESET of dimethyl to trimethyl lysine 9 of histone H3 to cause transcriptional repression. Mol. Cell 12, 475–487 (2003)

    Article  CAS  PubMed  Google Scholar 

  14. Balasubramani, A., Mukasa, R., Hatton, R. D. & Weaver, C. T. Regulation of the Ifng locus in the context of T-lineage specification and plasticity. Immunol. Rev. 238, 216–232 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Vaute, O., Nicolas, E., Vandel, L. & Trouche, D. Functional and physical interaction between the histone methyl transferase Suv39H1 and histone deacetylases. Nucleic Acids Res. 30, 475–481 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lighvani, A. A. et al. T-bet is rapidly induced by interferon-γ in lymphoid and myeloid cells. Proc. Natl Acad. Sci. USA 98, 15137–15142 (2001)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  17. Afkarian, M. et al. T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4+ T cells. Nature Immunol. 3, 549–557 (2002)

    Article  CAS  Google Scholar 

  18. Yamamoto, K. & Sonoda, M. Self-interaction of heterochromatin protein 1 is required for direct binding to histone methyltransferase, SUV39H1. Biochem. Biophys. Res. Commun. 301, 287–292 (2003)

    Article  CAS  PubMed  Google Scholar 

  19. Aagaard, L. et al. Functional mammalian homologues of the Drosophila PEV-modifier Su(var)3-9 encode centromere-associated proteins which complex with the heterochromatin component M31. EMBO J. 18, 1923–1938 (1999)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Eskeland, R., Eberharter, A. & Imhof, A. HP1 binding to chromatin methylated at H3K9 is enhanced by auxiliary factors. Mol. Cell. Biol. 27, 453–465 (2007)

    Article  CAS  PubMed  Google Scholar 

  21. Mateescu, B., England, P., Halgand, F., Yaniv, M. & Muchardt, C. Tethering of HP1 proteins to chromatin is relieved by phosphoacetylation of histone H3. EMBO Rep. 5, 490–496 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kumar, R. K., Herbert, C. & Foster, P. S. The ‘classical’ ovalbumin challenge model of asthma in mice. Curr. Drug Targets 9, 485–494 (2008)

    Article  CAS  PubMed  Google Scholar 

  23. Snapper, C. M., Peschel, C. & Paul, W. E. IFN-γ stimulates IgG2a secretion by murine B cells stimulated with bacterial lipopolysaccharide. J. Immunol. 140, 2121–2127 (1988)

    CAS  PubMed  Google Scholar 

  24. Gonzalo, J. A. et al. Eosinophil recruitment to the lung in a murine model of allergic inflammation. The role of T cells, chemokines, and adhesion receptors. J. Clin. Invest. 98, 2332–2345 (1996)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Romagnani, S. Immunologic influences on allergy and the TH1/TH2 balance. J. Allergy Clin. Immunol. 113, 395–400 (2004)

    Article  CAS  PubMed  Google Scholar 

  26. Barnes, P. J. The cytokine network in asthma and chronic obstructive pulmonary disease. J. Clin. Invest. 118, 3546–3556 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Barnes, P. J. Immunology of asthma and chronic obstructive pulmonary disease. Nature Rev. Immunol. 8, 183–192 (2008)

    Article  ADS  CAS  Google Scholar 

  28. Greiner, D., Bonaldi, T., Eskeland, R., Roemer, E. & Imhof, A. Identification of a specific inhibitor of the histone methyltransferase SU(VAR)3-9. Nature Chem. Biol. 1, 143–145 (2005)

    Article  CAS  Google Scholar 

  29. Lee, T. I., Johnstone, S. E. & Young, R. A. Chromatin immunoprecipitation and microarray-based analysis of protein location. Nature Protocols 1, 729–748 (2006)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are grateful to the late R. Losson for the generation of the HP1α-deficient mice. We acknowledge the members of the Department of Pathology and the Nikon Imaging Centre at the Institut Curie-CNRS. We thank T. Jenuwein for providing the SUV39H1-deficient mice and the members of INSERM U932 and CNRS UMR218 for discussions and suggestions. This work was supported by ANR-09-BLAN-0257 (‘ECens’), ANR 2010 1326 03 and HEALTH-F4-2010-257082 (from the European Commission Network of Excellence EpiGeneSys) to G.A., ANR 2009 BLAN-0021 EPIGO to F.C., and ANR 2010 BLAN-1326 01 and a grant from the Ligue National de Lutte contre le Cancer (Ligue équipe labélisée 2011–2013) to S.A. and E.Z. E.Z. and H.A.S. were funded by Fellowship of the Institut Curie (Paris), and R.S.A. was funded by an Australian National Health and Medical Research Council-INSERM fellowship (461286).

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Author notes

  1. Rhys S. Allan, Heidi A. Schreiber & Vanessa Masson

    Present address: Present addresses: Division of Molecular Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia (R.S.A.); Laboratory of Molecular Immunology and Rockefeller University, 1230 York Avenue, New York, New York 10065, USA (H.A.S.); Laboratory of Proteomic Mass Spectrometry, Institut Curie Research Center, 26 rue d’Ulm, 75248 Paris Cedex 05, France (V.M.).,

  2. Rhys S. Allan, Elina Zueva and Florence Cammas: These authors contributed equally to this work.

Authors and Affiliations

  1. Institut Curie Research Center, 26 rue d’Ulm, 75248 Paris Cedex 05, France ,

    Rhys S. Allan, Elina Zueva, Heidi A. Schreiber, Vanessa Masson, Danièle Roche, Christèle Maison, Jean-Pierre Quivy, Geneviève Almouzni & Sebastian Amigorena

  2. INSERM U932, Institut Curie Research Center, 26 rue d’Ulm, 75248 Paris Cedex 05, France ,

    Rhys S. Allan, Elina Zueva, Heidi A. Schreiber, Vanessa Masson & Sebastian Amigorena

  3. Institut de Recherche en Cancérologie de Montpellier, CRLC Val d’Aurelle-Paul Lamarque, 34298 Montpellier Cedex 5, France ,

    Florence Cammas

  4. Division of Molecular Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia,

    Gabrielle T. Belz

  5. CNRS UMR218, Institut Curie Research Center, 26 rue d’Ulm, 75248 Paris Cedex 05, France ,

    Danièle Roche, Christèle Maison, Jean-Pierre Quivy & Geneviève Almouzni

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Contributions

R.S.A., E.Z. and F.C. are joint first authors. R.S.A. and E.Z. designed the project, carried out experimental work and wrote the manuscript. F.C. carried out experimental work and interpreted data. H.A.S. carried out experimental work, analysed data and participated in data interpretation. V.M. and D.R. carried out experimental work. G.T.B. provided critical materials. C.M. and J.-P.Q. provided critical materials and wrote the manuscript. G.A. supervised the research and wrote the manuscript. S.A. conceived the project, supervised the research and wrote the manuscript.

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Correspondence to Rhys S. Allan or Sebastian Amigorena.

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The authors declare no competing financial interests.

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Allan, R., Zueva, E., Cammas, F. et al. An epigenetic silencing pathway controlling T helper 2 cell lineage commitment. Nature 487, 249–253 (2012). https://doi.org/10.1038/nature11173

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