美国哈佛医学院Diane Mathis团队近期取得重要工作进展，他们研究提出AIRE依靠Z-DNA标记胸腺T细胞耐受的基因靶标。相关研究成果2024年3月13日在线发表于《自然》杂志上。

据介绍，AIRE是一种非常规转录因子，可增强髓质胸腺上皮细胞中数千个基因的表达，并促进自身反应性T细胞的克隆缺失或表型转移。AIRE靶特异性的生物学逻辑在很大程度上仍不清楚，因为与许多转录因子相比，它不与特定的DNA序列基序结合。

研究人员采用了两种正交方法来研究AIRE的顺式调节机制：构建卷积神经网络和通过分析F1杂交小鼠利用自然遗传变异。这两种方法都认为Z-DNA和NFE2–MAF对AIRE的目标选择有积极影响。全基因组图谱研究表明，Z-DNA形成和NFE2L2结合基序与基因启动子产生DNA双链断裂的固有能力呈正相关，表现出强烈双链断裂产生的启动子更有可能进入可接近的染色质和已组装的转录机制的平稳状态。因此，AIRE优先靶向具有稳定启动子的基因。研究人员提出了一个模型，其中Z-DNA通过增强双链断裂的产生和启动子的定位来锚定AIRE介导的转录程序。

总之，这些发现除了能解决一个长期存在的机制难题外，还为操纵T细胞耐受性提供了途径。

附：英文原文

Title: AIRE relies on Z-DNA to flag gene targets for thymic T cell tolerization

Author: Fang, Yuan, Bansal, Kushagra, Mostafavi, Sara, Benoist, Christophe, Mathis, Diane

Issue&Volume: 2024-03-13

Abstract: AIRE is an unconventional transcription factor that enhances the expression of thousands of genes in medullary thymic epithelial cells and promotes clonal deletion or phenotypic diversion of self-reactive T cells1,2,3,4. The biological logic of AIRE’s target specificity remains largely unclear as, in contrast to many transcription factors, it does not bind to a particular DNA sequence motif. Here we implemented two orthogonal approaches to investigate AIRE’s cis-regulatory mechanisms: construction of a convolutional neural network and leveraging natural genetic variation through analysis of F1 hybrid mice5. Both approaches nominated Z-DNA and NFE2–MAF as putative positive influences on AIRE’s target choices. Genome-wide mapping studies revealed that Z-DNA-forming and NFE2L2-binding motifs were positively associated with the inherent ability of a gene’s promoter to generate DNA double-stranded breaks, and promoters showing strong double-stranded break generation were more likely to enter a poised state with accessible chromatin and already-assembled transcriptional machinery. Consequently, AIRE preferentially targets genes with poised promoters. We propose a model in which Z-DNA anchors the AIRE-mediated transcriptional program by enhancing double-stranded break generation and promoter poising. Beyond resolving a long-standing mechanistic conundrum, these findings suggest routes for manipulating T cell tolerance.

DOI: 10.1038/s41586-024-07169-7

Source: https://www.nature.com/articles/s41586-024-07169-7