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Z-DNA underlies the target choice of Aire by facilitating promoter poising

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE224557 | GEO | 2024/03/11

REPOSITORIES: GEO

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Z-DNA underlies the target choice of Aire by facilitating promoter poising [ChIPmentation]

Project description:We profiled NELF and Aire binding in medullary thymic epithelial cells using ChIPmentation to investigate the logic of Aire's target choices

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Z-DNA underlies the target choice of Aire by facilitating promoter poising [BLISS]

Project description:We profiled DNA double-strand break (DSB) formation genome-wide in medullary thymic epithelial cells to investigate how DSBs regulate Aire's target choices

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Z-DNA underlies the target choice of Aire by facilitating promoter poising [RNA-seq]

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Z-DNA underlies the target choice of Aire by facilitating promoter poising [ATAC-seq]

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Z-DNA underlies the target choice of Aire by facilitating promoter poising [CUT&Tag]

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Z-DNA underlies the target choice of Aire by facilitating promoter poising [ChIP-seq]

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Z-DNA underlies the target choice of Aire by facilitating promoter poising [scRNA-Seq]

Project description:Aire is an unconventional transcription factor (TF) that enhances the expression of thousands of genes in medullary thymic epithelial cells (mTECs), which promotes clonal deletion or phenotypic diversion of self-reactive T cells. The biological logic of Aire’s target specificity remains largely unknown as, unlike many TFs, it does not bind to a particular DNA-sequence motif. We implemented two orthogonal approaches to investigate Aire’s cis-regulatory mechanisms: construction of a convolutional neural network and leveraging of natural genetic variation via analysis of F1-hybrid mice. 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-strand breaks (DSBs), and promoters showing strong DSB generation were more likely to enter a poised state with accessible chromatin and already-assembled transcriptional machinery. Consequently, Aire preferentially targeted genes with poised promoters. We propose a model whereby Z-DNA anchors the Aire-mediated transcriptional program by enhancing DSB generation and promoter poising. Beyond resolving a long-standing mechanistic conundrum, these findings suggest previously unexplored routes of manipulating T-cell tolerance.

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