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An epigenetic silencing pathway controlling T helper 2 cell lineage commitment

机译：表观遗传沉默途径控制T辅助2细胞沿袭承诺

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摘要

During immune responses, naive CD4~+ T cells differentiate into several T helper (T_H) cell subsets under the control of lineage-specifying genes. These subsets (T_H1, T_H2 and T_H17 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 differentiation. Nevertheless, the functional relevance of the epigenetic pathways involved in T_H cell subset differentiation and commitment is still unclear. Here we explore the role of the SUV39H1-H3K9me3-HPlα silencing pathway in the control of T_H2 lineage stability. This pathway involves the histone methylase SUV39H1, which participates in the trimethyla-tion of histone H3 on lysine 9 (H3K9me3), a modification that provides binding sites for heterochromatin protein la (HP1α) and promotes transcriptional silencing. This pathway was initially associated with heterochromatin formation and maintenance but can also contribute to the regulation of euchromatic genes. We now propose that the SUV39Hl-H3K9me3-HPla pathway participates in maintaining the silencing of T_H1 loci, ensuring T_H2 lineage stability. In T_H2 cells that are deficient in SUV39H1, the ratio between trimethylated and acetylated H3K9 is impaired, and the binding of HPla at the promoters of silenced T_H1 genes is reduced. Despite showing normal differentiation, both SUV39H1-deficient T_H2 cells and HP1α-deficient T_H2 cells, in contrast to wild-type cells, expressed T_H1 genes when recultured under conditions that drive differentiation into T_H1 cells. In a mouse model of T_H2-driven allergic asthma, the chemical inhibition or loss of SUV39H1 skewed T-cell responses towards T_H1 responses and decreased the lung pathology. These results establish a link between the SUV39H1-H3K9me3-HPla pathway and the stability of T_H2 cells, and they identify potential targets for therapeutic intervention in T_H2-cell-mediated inflammatory diseases.
机译：在免疫应答过程中，幼稚的CD4〜+ T细胞在沿袭特异性基因的控制下分化为几个T辅助（T_H）细胞亚群。这些亚群（T_H1，T_H2和T_H17细胞和调节性T细胞）分泌不同的细胞因子，并参与针对不同类型感染的保护。表观遗传机制参与了这些发育程序的调控，并且在表观遗传标记的水平与分化过程中特定基因的活性或沉默之间已经建立了相关性。然而，尚不清楚与T_H细胞亚群分化和定型有关的表观遗传途径的功能相关性。在这里，我们探讨了SUV39H1-H3K9me3-HPlα沉默途径在控制T_H2谱系稳定性中的作用。该途径涉及组蛋白甲基化酶SUV39H1，它参与赖氨酸9（H3K9me3）上组蛋白H3的三甲基化作用，该修饰为异染色质蛋白la（HP1α）提供结合位点并促进转录沉默。该途径最初与异染色质的形成和维持有关，但也可能有助于常染色体基因的调控。我们现在提出SUV39H1-H3K9me3-HPla途径参与维持T_H1基因座的沉默，确保T_H2谱系的稳定性。在缺乏SUV39H1的T_H2细胞中，三甲基化和乙酰化的H3K9之间的比例受损，并且HPla在沉默的T_H1基因的启动子上的结合减少。尽管显示出正常的分化，但与野生型细胞相比，缺乏SUV39H1的T_H2细胞和缺乏HP1α的T_H2细胞在驱动分化为T_H1细胞的条件下进行再培养时仍表达T_H1基因。在由T_H2驱动的过敏性哮喘的小鼠模型中，SUV39H1的化学抑制或丢失使T细胞反应偏向T_H1反应并降低了肺部病理。这些结果在SUV39H1-H3K9me3-HPla途径与T_H2细胞的稳定性之间建立了联系，并且它们确定了治疗干预T_H2细胞介导的炎性疾病的潜在靶标。

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  • 来源
    《Nature》 |2012年第7406期|p.249-253|共5页
  • 作者

    Rhys S. Allan; Elina Zueva; Florence Cammas; Heidi A. Schreiber; Vanessa Masson; Gabrielle T. Belz; Daniele Roche; Christele Maison; Jean-Pierre Quivy; Genevieve Almouzni; Sebastian Amigorena;

  • 作者单位

    Institut Curie Research Center, 26 rue d'Ulm, 75248 Paris Cedex 05, France,INSERM U932, Institut Curie Research Center, 26 rue d'Ulm, 75248 Paris Cedex 05, France,Division of Molecular Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia;

    Institut Curie Research Center, 26 rue d'Ulm, 75248 Paris Cedex 05, France,INSERM U932, Institut Curie Research Center, 26 rue d'Ulm, 75248 Paris Cedex 05, France;

    lnstitut de Recherche en Cancerologie de Montpellier, CRLC Val d'Aurelle-Paul Lamarque, 34298 Montpeltier Cedex 5, France;

    Institut Curie Research Center, 26 rue d'Ulm, 75248 Paris Cedex 05, France,INSERM U932, Institut Curie Research Center, 26 rue d'Ulm, 75248 Paris Cedex 05, France,Laboratory of Molecular Immunology and Rockefeller University, 1230 York Avenue, New York, New York 10065, USA;

    Institut Curie Research Center, 26 rue d'Ulm, 75248 Paris Cedex 05, France,INSERM U932, Institut Curie Research Center, 26 rue d'Ulm, 75248 Paris Cedex 05, France,Laboratory of Proteomic Mass Spectrometry, Institut Curie Research Center, 26 rue d'Ulm, 75248 Paris Cedex 05, France;

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

    Institut Curie Research Center, 26 rue d'Ulm, 75248 Paris Cedex 05, France,CNRS UMR218, InstitutCurie Research Center, 26 rue d'Ulm, 75248 Paris Cedex 05, France;

    Institut Curie Research Center, 26 rue d'Ulm, 75248 Paris Cedex 05, France,CNRS UMR218, InstitutCurie Research Center, 26 rue d'Ulm, 75248 Paris Cedex 05, France;

    Institut Curie Research Center, 26 rue d'Ulm, 75248 Paris Cedex 05, France,CNRS UMR218, InstitutCurie Research Center, 26 rue d'Ulm, 75248 Paris Cedex 05, France;

    Institut Curie Research Center, 26 rue d'Ulm, 75248 Paris Cedex 05, France,CNRS UMR218, InstitutCurie Research Center, 26 rue d'Ulm, 75248 Paris Cedex 05, France;

    Institut Curie Research Center, 26 rue d'Ulm, 75248 Paris Cedex 05, France,INSERM U932, Institut Curie Research Center, 26 rue d'Ulm, 75248 Paris Cedex 05, France;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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