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. Hi-C analyses revealed inducible TADs that insulated and enhancers during Th1 cell differentiation. Targeted deletion of a 17 bp boundary motif of these TADs imbalanced Th1- and Th17-associated immunity, both and , upon 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.

中文翻译：

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Mdm1-Il22-Ifng 基因座中的 CTCF 结合位点塑造细胞因子表达谱，并在早期 Th1 细胞命运规范中发挥关键作用


T 细胞分化过程中的细胞因子表达是一个高度调控的过程，涉及细胞因子位点的长程启动子增强子和 CTCF-CTCF 接触。在这里，我们研究了拓扑关联域 (TAD) 内动态染色质环形成对调节干扰素 γ (IFN-γ) 和白细胞介素 22 (IL-22) 表达的影响；这些细胞因子位点紧密位于基因组中，并与复杂的增强子景观相关，这些增强子景观在 1 型和 3 型淋巴细胞中选择性活跃。 Hi-C 分析揭示了诱导型 TAD 在 Th1 细胞分化过程中起到绝缘作用和增强作用。感染后，有针对性地删除这些 TAD 的 17 bp 边界基序会导致 Th1 和 Th17 相关免疫失衡。相反，这个边界元素对于自然杀伤细胞中的细胞因子调节来说是可有可无的。我们的研究结果表明，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。