Institut Curie Research Center, 26 rue d’Ulm, 75248 Paris Cedex 05, France.
Nature. 2012 Jul 12;487(7406):249-53. doi: 10.1038/nature11173.
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 differentiation. 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) 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 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.
在免疫反应中，幼稚 CD4+T 细胞在谱系特异性基因的控制下分化为几种 T 辅助（TH）细胞亚群。这些亚群（TH1、TH2 和 TH17 细胞和调节性 T 细胞）分泌不同的细胞因子，参与对抗不同类型的感染。表观遗传机制参与这些发育程序的调节，并且已经在分化过程中特定表观遗传标记的水平与指定基因的活性或沉默之间建立了相关性。然而，参与 TH 细胞亚群分化和定型的表观遗传途径的功能相关性仍然不清楚。在这里，我们探讨了 SUV39H1-H3K9me3-HP1α 沉默途径在控制 TH2 谱系稳定性中的作用。该途径涉及组蛋白甲基转移酶 SUV39H1，它参与赖氨酸 9（H3K9me3）上组蛋白 H3 的三甲基化，该修饰为异染色质蛋白 1α（HP1α）提供结合位点并促进转录沉默。该途径最初与异染色质形成和维持有关，但也可以有助于调节常染色质基因。我们现在提出，SUV39H1-H3K9me3-HP1α 途径参与维持 TH1 基因座的沉默，确保 TH2 谱系的稳定性。在 SUV39H1 缺乏的 TH2 细胞中，三甲基化和乙酰化 H3K9 的比例受损，并且沉默的 TH1 基因启动子处的 HP1α 结合减少。尽管表现出正常分化，但与野生型细胞相比，SUV39H1 缺陷型 TH2 细胞和 HP1α 缺陷型 TH2 细胞在重新培养条件下分化为 TH1 细胞时都表达 TH1 基因。在 TH2 驱动的过敏性哮喘的小鼠模型中，SUV39H1 的化学抑制或缺失使 T 细胞反应偏向 TH1 反应，并减少了肺部病理学。这些结果在 SUV39H1-H3K9me3-HP1α 途径和 TH2 细胞的稳定性之间建立了联系，并确定了 TH2 细胞介导的炎症性疾病治疗干预的潜在靶点。
