Trithorax Cxxc1-directed epigenetic dynamics licensing CD4+ T cell differentiation. Trithorax Cxxc1-directed epigenetic dynamics licensing CD4+ T cell differentiation

Different dynamics of gene expression are observed during cell differentiation. In T-cells, genes that are turned on early, or turned off and stay off have been thoroughly studied. However, genes that are initially turned off but then turned on again after stimulation has ceased have not been defined; they are obviously important, especially in the context of acute versus chronic inflammation. Using the Th1/Th2 differentiation paradigm, we found that Cxxc1 subunit of the Trithorax complex directs transcription of genes initially downregulated by TCR stimulation but upregulated again in a later phase. The late upregulation of these genes was impaired either by prolonged TCR stimulation or Cxxc1-deficiency, which led to decreased expression of Trib3 and Klf2 in Th1 and Th2 cells, respectively. Loss of Cxxc1 resulted in enhanced pathogenicity in allergic airway inflammation in vivo. Thus, Cxxc1 plays essential roles in the establishment of a proper CD4+ T-cell immune system via epigenetic control of a specific set of genes. Overall design: Different dynamics of gene expression during T cell differentiation assessed by ATAC-seq, ChIP-seq and RNA-seq.

细胞分化过程中可观察到不同的基因表达动态模式。在T细胞中，早期激活或初始关闭并持续维持沉默状态的基因已得到充分研究。然而，那些初始处于沉默状态、却在刺激终止后再度激活的基因尚未被明确界定；这类基因显然具有重要功能，尤其在急性与慢性炎症的研究背景中。本研究借助Th1/Th2分化模型开展实验，发现Trithorax复合物的Cxxc1亚基可调控那些经T细胞受体（TCR）刺激后初始下调、却在后续阶段再度上调的基因的转录。无论是延长TCR刺激时长还是敲除Cxxc1，都会削弱这类基因的后期上调过程，进而分别导致Th1与Th2细胞中Trib3及Klf2的表达水平下降。体内实验显示，Cxxc1的缺失会加剧过敏性气道炎症的致病效应。综上，Cxxc1通过表观遗传调控特定基因集，在构建正常的CD4+ T细胞免疫系统中发挥关键作用。实验整体设计：通过ATAC-seq、ChIP-seq及RNA-seq技术，对T细胞分化过程中的基因表达动态模式进行评估。