CXXC finger protein 1 is critical for T cell intrathymic development through regulating H3K4 trimethylation [RNA-Seq]

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 RORgammat and for TCR signaling including Zap70 and CD8, through maintaining the appropriate H3K4me3 on their promoters. Importantly, we show that RORgammat, 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. RNA-Seq analysis of WT and Cxxc1-deficient mice胸腺中T细胞的发育过程主要由同时涉及DNA甲基化与组蛋白修饰的表观遗传程序所调控。既往研究已将Cxxc1鉴定为胞嘧啶甲基化与组蛋白3赖氨酸4三甲基化（H3K4me3）的调控因子。然而，目前尚不清楚Cxxc1是否在胸腺细胞发育中发挥作用。本研究发现，Cxxc1缺陷小鼠的胸腺T细胞发育受到严重损伤。此外，我们在野生型与Cxxc1缺陷型胸腺细胞中鉴定了全基因组范围内的Cxxc1结合位点与H3K4me3修饰位点。本研究结果表明，Cxxc1可通过维持其靶基因启动子上适宜水平的H3K4me3修饰，直接调控胸腺细胞存活关键基因（如RORγt）以及T细胞受体（TCR）信号通路相关基因（包括Zap70与CD8）的表达。尤为重要的是，我们证实作为Cxxc1直接靶标的RORγt能够挽救Cxxc1缺陷型胸腺细胞的存活缺陷。本研究数据有力支持Cxxc1在胸腺细胞发育中发挥关键调控作用。本研究对野生型与Cxxc1缺陷型小鼠开展了RNA测序（RNA-Seq）分析。