PDF(Pubmed)
Abstract：
Cytokine expression during T cell differentiation is a highly regulated process that involves long-range promoter-enhancer and CTCF-CTCF contacts at cytokine loci. Here, we investigated the impact of dynamic chromatin loop formation within the topologically associating domain (TAD) in regulating the expression of interferon gamma (IFN-γ) and interleukin-22 (IL-22); these cytokine loci are closely located in the genome and are associated with complex enhancer landscapes, which are selectively active in type 1 and type 3 lymphocytes. In situ Hi-C analyses revealed inducible TADs that insulated Ifng and Il22 enhancers during Th1 cell differentiation. Targeted deletion of a 17 bp boundary motif of these TADs imbalanced Th1- and Th17-associated immunity, both in vitro and in vivo, upon Toxoplasma gondii infection. In contrast, this boundary element was dispensable for cytokine regulation in natural killer cells. Our findings suggest that precise cytokine regulation relies on lineage- and developmental stage-specific interactions of 3D chromatin architectures and enhancer landscapes.
摘要：
T细胞分化过程中的细胞因子表达是一个高度调节的过程，涉及长范围启动子-增强子和CTCF-CTCF在细胞因子基因座处的接触。这里,我们研究了拓扑关联域（TAD）内动态染色质环形成在调节干扰素γ（IFN-γ）和白介素-22（IL-22）表达中的影响;这些细胞因子基因座紧密位于基因组中，并与复杂的增强子景观相关，在1型和3型淋巴细胞中选择性活跃。原位Hi-C分析显示，诱导型TAD在Th1细胞分化过程中隔离了Ifng和Il22增强子。靶向删除这些TAD不平衡Th1和Th17相关免疫的17bp边界基序，在体外和体内，弓形虫感染。相比之下,该边界元素对于自然杀伤细胞中的细胞因子调节是不必要的。我们的发现表明，精确的细胞因子调节依赖于3D染色质结构和增强子景观的谱系和发育阶段特异性相互作用。
