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

Yuan Fang, Kushagra Bansal, Sara Mostafavi, Christophe Benoist and Diane Mathis ()
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Yuan Fang: Harvard Medical School
Kushagra Bansal: Jawaharlal Nehru Centre for Advanced Scientific Research
Sara Mostafavi: University of Washington
Christophe Benoist: Harvard Medical School
Diane Mathis: Harvard Medical School

Nature, 2024, vol. 628, issue 8007, 400-407

Abstract: 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 cells1–4. 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.

Date: 2024
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DOI: 10.1038/s41586-024-07169-7

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