Aire controls immunological tolerance by driving promiscuous expression of a large swath of the genome in medullary thymic epithelial cells (mTECs). Its molecular mechanism remains enigmatic. High-resolution chromosome-conformation capture (Hi-C) experiments on ex vivo mTECs revealed Aire to have a widespread impact on higher-order chromatin structure, disfavoring architectural loops while favoring transcriptional loops. In the presence of Aire, cohesin complexes concentrated on superenhancers together with mediator complexes, while the CCCTC-binding factor (CTCF) was relatively depleted from structural domain boundaries. In particular, Aire associated with the cohesin loader, NIPBL, strengthening this factor’s affiliation with cohesin’s enzymatic subunits. mTEC transcripts up-regulated in the presence of Aire corresponded closely to those down-regulated in the absence of one of the cohesin subunits, SA-2. A mechanistic model incorporating these findings explains many of the unusual features of Aire’s impact on mTEC transcription, providing molecular insight into tolerance induction.

Aire 通过驱动胸腺髓质上皮细胞 (mTEC) 中大量基因组的混杂表达来控制免疫耐受。其分子机制仍然是个谜。对离体 mTEC 进行的高分辨率染色体构象捕获 (Hi-C) 实验表明，Aire 对高阶染色质结构具有广泛的影响，不利于结构环，而有利于转录环。在 Aire 存在的情况下，粘连蛋白复合物与介体复合物一起集中在超级增强子上，而 CCCTC 结合因子 (CTCF) 从结构域边界相对耗尽。特别是，Aire 与粘连蛋白装载机 NIPBL 相关，加强了该因子与粘连蛋白酶亚基的联系。在 Aire 存在的情况下 mTEC 转录本的上调与在粘连蛋白亚基之一 SA-2 不存在的情况下下调的转录本密切相关。结合这些发现的机制模型解释了 Aire 对 mTEC 转录影响的许多不寻常特征，为耐受诱导提供了分子洞察。