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

• 成果类型: Article
• 署名作者: Fang, Yuan; Bansal, Kushagra; Mostafavi, Sara; Benoist, Christophe; Mathis, Diane
• 署名单位: Harvard University; Harvard Medical School; Harvard University; Department of Science & Technology (India); Jawaharlal Nehru Center for Advanced Scientific Research (JNCASR); University of Washington; University of Washington Seattle; Canadian Institute for Advanced Research (CIFAR)
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4737
• DOI: 10.1038/s41586-024-07169-7
• 发表日期: 2024-04-11
• 关键词: topoisomerase-i; b-dna; expression patterns; chip-seq; transcription; chromatin; reveals; activation; polymerase; population

摘要

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 cells1-4. 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. Z-DNA anchors the AIRE-mediated transcriptional program by enhancing the generation of double-stranded breaks and promoter poising.