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

• Published in: Nature communications Vol. 7; no. 1; pp. 11687 - 11
• Main Authors: Cao, Wenqiang, Guo, Jing, Wen, Xiaofeng, Miao, Li, Lin, Feng, Xu, Guanxin, Ma, Ruoyu, Yin, Shengxia, Hui, Zhaoyuan, Chen, Tingting, Guo, Shixin, Chen, Wei, Huang, Yingying, Liu, Yizhi, Wang, Jianli, Wei, Lai, Wang, Lie
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.05.2016; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250/1619/554; 631/250/1620/1840; 631/250/516; 631/337/458/1648; Animals; Binding sites; CD8 Antigens - metabolism; Cell Line; Cell Survival; DNA methylation; Epigenesis, Genetic; Epigenetics; Gene expression; Genomes; Histones - metabolism; Humanities and Social Sciences; Immunology; Mice; Mice, Knockout; multidisciplinary; Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism; Proteins; Receptors, Antigen, T-Cell - metabolism; Science; Science (multidisciplinary); Thymocytes - physiology; Thymus gland; Trans-Activators - physiology; ZAP-70 Protein-Tyrosine Kinase - metabolism; Pittsburgh Pennsylvania; United States > US; China; Pennsylvania
• DOI: 10.1038/ncomms11687
• ISSN: 2041-1723

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.