An epigenetic silencing pathway controlling T helper 2 cell lineage commitment.
An epigenetic silencing pathway controlling T helper 2 cell lineage commitment.
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DOI：
10.1038/nature11173
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发表时间：
2012-07-12
期刊：
影响因子：
64.8
通讯作者：
Amigorena, Sebastian
中科院分区：
文献类型：
--
作者：
Allan, Rhys S;Zueva, Elina;Amigorena, Sebastian
在免疫应答过程中，初始CD 4 + T细胞在谱系特异性基因的控制下分化成几个T辅助（TH）细胞亚群。这些亚群（TH 1、TH 2和TH 17细胞以及调节性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节，并且已经在特定表观遗传标记的水平与分化期间指定基因的活性或沉默之间绘制了相关性。然而，TH细胞亚群分化和定型中所涉及的表观遗传途径的功能相关性仍不清楚。在这里，我们探讨了SUV 39 H1-H3 K9 me 3-HP 1 α沉默途径在TH 2谱系稳定性控制中的作用。该途径涉及组蛋白甲基化酶SUV 39 H1，其参与组蛋白H3在赖氨酸9（H3 K9 me 3）上的三甲基化，这是一种为异染色质蛋白1 α（HP 1 α）提供结合位点并促进转录沉默的修饰。该途径最初与异染色质的形成和维持有关，但也有助于常染色质基因的调节。我们现在提出，SUV 39 H1-H3 K9 me 3-HP 1 α通路参与维持TH 1基因座的沉默，确保TH 2谱系的稳定性。在缺乏SUV 39 H1的TH 2细胞中，三甲基化和乙酰化H3 K9之间的比率受损，并且HP 1 α在沉默的TH 1基因的启动子处的结合减少。尽管显示正常分化，但与野生型细胞相反，SUV 39 H1缺陷型TH 2细胞和HP 1 α缺陷型TH 2细胞在驱动分化为TH 1细胞的条件下再培养时表达TH 1基因。在TH 2驱动的过敏性哮喘的小鼠模型中，SUV 39 H1的化学抑制或丧失使T细胞应答偏向TH 1应答，并降低肺病理学。这些结果建立了SUV 39 H1-H3 K9 me 3-HP 1alpha通路与TH 2细胞稳定性之间的联系，并确定了TH 2细胞介导的炎性疾病治疗干预的潜在靶点。
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-HP1alpha 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 1alpha (HP1alpha) 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-HP1alpha 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 HP1alpha at the promoters of silenced TH1 genes is reduced. Despite showing normal differentiation, both SUV39H1-deficient TH2 cells and HP1alpha-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-HP1alpha pathway and the stability of TH2 cells, and they identify potential targets for therapeutic intervention in TH2-cell-mediated inflammatory diseases.