Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Eur J Immunol. 2012 Sep;42(9):2471-83. doi: 10.1002/eji.201142307. Epub 2012 Jul 13.
Anergy is induced in T cells as a consequence of a partial or suboptimal stimulation. Anergic T cells become unresponsive and fail to proliferate and produce cytokines. We had previously shown that in anergic CD4(+) T cells, Ikaros participates in the transcriptional repression of the Il2 gene by recruiting histone deacetylases that cause core histone deacetylation at the Il2 promoter. Here we show that deacetylation at the Il2 promoter is the initial step in a process that leads to the stable silencing of the Il2 gene transcription in anergic T cells. We have found that anergy-induced deacetylation of the Il2 promoter permits binding of the histone methyl-transferase Suv39H1, which trimethylates lysine-9 of histone H3 (Me3H3-K9). Furthermore, the establishment of the Me3H3-K9 mark allows the recruitment of the heterochromatin protein HP1, allowing the silenced Il2 loci to reposition close to heterochromatin-rich regions. Our results indicate that silencing of Il2 transcription in anergic T cells is attained through a series of epigenetic changes that involve the establishment of repressive marks and the subsequent nuclear repositioning of the Il2 loci, which become juxtaposed to transcriptionally silent regions. This mechanism may account for the stable nature of the inhibition of IL-2 production in anergic cells.
无能是由于部分或不完全刺激导致 T 细胞产生的。无能的 T 细胞变得无反应，无法增殖和产生细胞因子。我们之前曾表明，在无能的 CD4(+) T 细胞中，Ikaros 通过招募组蛋白去乙酰化酶参与 Il2 基因的转录抑制，导致 Il2 启动子核心组蛋白去乙酰化。在这里，我们表明 Il2 启动子的去乙酰化是导致无能 T 细胞中 Il2 基因转录稳定沉默的过程中的初始步骤。我们发现，无能诱导的 Il2 启动子去乙酰化允许组蛋白甲基转移酶 Suv39H1 结合，该酶将组蛋白 H3 的赖氨酸-9 三甲基化 (Me3H3-K9)。此外，Me3H3-K9 标记的建立允许异染色质蛋白 HP1 的募集，允许沉默的 Il2 基因座重新定位到富含异染色质的区域附近。我们的结果表明，无能 T 细胞中 Il2 转录的沉默是通过一系列涉及建立抑制性标记和随后 Il2 基因座的核重新定位的表观遗传变化实现的，这些变化与转录沉默区域并置。这种机制可能解释了无能细胞中 IL-2 产生抑制的稳定性。
