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

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

PROVIDER: PRJNA934447 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23343605_1.fastq.gz	Fastqsanger.gz
	SRR23343605_2.fastq.gz	Fastqsanger.gz
	SRR23343606_1.fastq.gz	Fastqsanger.gz
	SRR23343606_2.fastq.gz	Fastqsanger.gz
	SRR23343607_1.fastq.gz	Fastqsanger.gz

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

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

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