Systematic mapping of enhancers, silencers, and topological elements with prime editing deletion screens
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Noncoding regulatory elements in the human genome can control gene expression through distinct mechanisms, including acting as enhancers, silencers, or topological elements. However, we lack tools to identify all such classes systematically and quantify their effects on gene expression in an endogenous genomic context. Here we develop Swap-seq, a method that combines pooled twin prime editing with flow-sorting to delete hundreds of endogenous regulatory sequences and measure their quantitative effects on the expression of a nearby gene. We apply Swap-seq to dissect the regulatory elements that control PPIF expression in THP-1 monocytes. We quantify the effects of distal and intronic enhancers, characterize CTCF insulators, and discover a silencer that regulates distal genes through histone deacetylase (HDAC)-mediated repression of neighboring enhancers. Hundreds of other genomic elements share its chromatin signatures and transcription factor binding sites, suggesting that this silencer represents a broader class of repressive elements. We leverage Swap-seq data to benchmark sequence-to-function models and show that they often capture the local activity of regulatory elements but fail to link them to distal target genes. Swap-seq thus provides a generalizable tool to discover regulatory elements across mechanistic classes, characterize their effects on gene expression, and generate large-scale datasets for evaluating sequence-to-function models.
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This one is moving fast on JClub: Swap-seq enables systematic deletion and quantification of hundreds of endogenous regulatory elements, revealing their diverse effects on gene expression in human cells. doi.org/10.64898/2026.10.08.756856
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Cai et al. develop Swap-seq, pairing pooled twin prime editing with flow sorting to delete hundreds of regulatory elements at PPIF in THP-1 monocytes, quantifying enhancers and CTCF insulators and uncovering an HDAC-dependent silencer that represses neighboring enhancers.
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Systematic mapping of enhancers, silencers, and topological elements using prime editing deletion screens www.biorxiv.org/content/10.6... Check out our preprint on next-generation tech for mapping distal regulatory effects! We’re excited to help set this up - please get in touch Thread 👇
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Have you ever looked at a gene in IGV or a genome browser and wondered “What are all those (ATAC-seq/H3K27ac/CTCF ChIP-seq/…) peaks doing?” 🤔 I’m thrilled to share that we developed a new technology called Swap-seq to answer that exact question. Swap-seq: www.biorxiv.org/content/10.6...
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Systematic mapping of enhancers, silencers, and topological elements with prime editing deletion screens https://www.biorxiv.org/content/10.64898/2026.10.08.756856v1
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Systematic mapping of enhancers, silencers, and topological elements with prime editing deletion screens https://www.biorxiv.org/content/10.64898/2026.10.08.756856v1
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