The deficiency of Aire, a transcriptional regulator whose defect results in the development of autoimmunity, is associated with reduced expression of tissue-restricted self-Ags (TRAs) in medullary thymic epithelial cells (mTECs). Although the mechanisms underlying Aire-dependent expression of TRAs need to be explored, the physical identification of the target(s) of Aire has been hampered by the low and promiscuous expression of TRAs. We have tackled this issue by engineering mice with augmented Aire expression. Integration of the transcriptomic data from Aire-augmented and Aire-deficient mTECs revealed that a large proportion of so-called Aire-dependent genes, including those of TRAs, may not be direct transcriptional targets downstream of Aire. Rather, Aire induces TRA expression indirectly through controlling the heterogeneity of mTECs, as revealed by single-cell analyses. In contrast, Ccl25 emerged as a canonical target of Aire, and we verified this both in vitro and in vivo. Our approach has illuminated the Aires primary targets while distinguishing them from the secondary targets.
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机译：Aire是一种转录调节因子，其缺陷导致自身免疫的发展，其缺乏与髓质胸腺上皮细胞（mTECs）中组织限制性自抗原（TRA）的表达降低有关。尽管需要探索 TRA 的 Aire 依赖性表达机制，但 TRA 的低表达和混杂表达阻碍了 Aire 靶标的物理鉴定。我们通过对小鼠进行增强的Aire表达来解决这个问题。整合来自 Are 增强和 Are 缺陷 mTEC 的转录组学数据表明，很大一部分所谓的 Are 依赖性基因，包括 TRA 的基因，可能不是 Are 下游的直接转录靶标。相反，正如单细胞分析所揭示的那样，Aire 通过控制 mTEC 的异质性间接诱导 TRA 表达。相比之下，Ccl25 成为 Aire 的典型靶点，我们在体外和体内都验证了这一点。我们的方法阐明了艾利斯的主要目标，同时将它们与次要目标区分开来。
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