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An epigenetic silencing pathway controlling T helper 2 cell lineage commitment

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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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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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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This file contains Supplementary Figures 1-10 and Supplementary Table 1 with additional references. (PDF 9820 kb)

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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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