CXXC finger protein 1 is critical for T-cell intrathymic development through regulating H3K4 trimethylation.
CXXC finger protein 1 is critical for T-cell intrathymic development through regulating H3K4 trimethylation.
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CXXC 指蛋白 1 通过调节 H3K4 三甲基化对 T 细胞胸腺内发育至关重要。
DOI：
10.1038/ncomms11687
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发表时间：
2016-05-23
影响因子：
16.6
通讯作者：
Wang L
中科院分区：
文献类型：
--
作者：
Cao W;Guo J;Wen X;Miao L;Lin F;Xu G;Ma R;Yin S;Hui Z;Chen T;Guo S;Chen W;Huang Y;Liu Y;Wang J;Wei L;Wang L
胸腺中 T 细胞的发育很大程度上受表观遗传程序控制，涉及 DNA 甲基化和组蛋白修饰。先前的研究已确定 Cxxc1 是胞嘧啶甲基化和组蛋白 3 赖氨酸 4 三甲基化 (H3K4me3) 的调节因子。然而，Cxxc1 是否在胸腺细胞发育中发挥作用尚不清楚。在这里，我们发现 Cxxc1 缺陷小鼠的胸腺 T 细胞发育严重受损。此外，我们在野生型和 Cxxc1 缺陷胸腺细胞中鉴定了全基因组 Cxxc1 结合位点和 H3K4me3 修饰位点。我们的结果表明，Cxxc1 通过在其启动子上维持适当的 H3K4me3，直接控制对胸腺细胞存活（如 RORγt）和 T 细胞受体信号传导（包括 Zap70 和 CD8）重要的关键基因的表达。重要的是，我们发现 RORγt 作为 Cxxc1 的直接靶点，可以挽救 Cxxc1 缺陷型胸腺细胞的生存缺陷。我们的数据强烈支持 Cxxc1 在胸腺细胞发育中的关键作用。 T 细胞发育一直是了解表观遗传学细胞命运调控的经典模型。作者在此表明，Cxxc1主要通过调节Rorc、Zap70和Cd8等几个关键基因来控制胸腺细胞发育，这需要其H3K4me3而不是DNA甲基化功能。
T-cell development in the thymus is largely controlled by an epigenetic program, involving in both DNA methylation and histone modifications. Previous studies have identified Cxxc1 as a regulator of both cytosine methylation and histone 3 lysine 4 trimethylation (H3K4me3). However, it is unknown whether Cxxc1 plays a role in thymocyte development. Here we show that T-cell development in the thymus is severely impaired in Cxxc1-deficient mice. Furthermore, we identify genome-wide Cxxc1-binding sites and H3K4me3 modification sites in wild-type and Cxxc1-deficient thymocytes. Our results demonstrate that Cxxc1 directly controls the expression of key genes important for thymocyte survival such as RORγt and for T-cell receptor signalling including Zap70 and CD8, through maintaining the appropriate H3K4me3 on their promoters. Importantly, we show that RORγt, a direct target of Cxxc1, can rescue the survival defects in Cxxc1-deficient thymocytes. Our data strongly support a critical role of Cxxc1 in thymocyte development. T cell development has been a classical model for understanding cell fate regulation by epigenetics. Here the authors show that Cxxc1 controls thymocyte development mainly through regulating several key genes, such as Rorc, Zap70 and Cd8, which requires its H3K4me3 but not DNA methylation function.