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bioRxiv · 10.1101/2025.10.14.682013

Enhancer-promoter compatibility is mediated by the promoter-proximal region

Majchrzycka, B. M.·Mundlos, S.·Krebs, A.·Ibrahim, D. M.
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Abstract

Gene promoters induce transcription in response to distal enhancers. How enhancers specifically activate their target promoter while bypassing other promoters remains unclear. Here, we find that the promoter-proximal region is critical for cell-type specific enhancer-promoter compatibility. Using high-throughput genome-engineering in mouse embryonic stem cells (mESC), we systematically replace the endogenous Sox9 promoter with different libraries of core and extended (i.e. full) promoters and assess their response to long-range regulatory elements in mESCs and neural progenitor cells. We find that only a subset of full promoters is activated by distal neuronal enhancers and that the promoter-proximal region is necessary for this enhancer-promoter compatibility. Core promoters alone are insufficient to respond to distal enhancers but modulate the transcriptional output of responsive promoters. Our results suggest that within multipartite regulatory domains, the promoter-proximal region fulfills a facilitator-like function that filters and transmits signal from distal enhancers, ultimaltely conferring enhancer-promoter compatibility.

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Majchrzycka, B. M., Mundlos, S., Krebs, A., Ibrahim, D. M.. 2025-10-15. Enhancer-promoter compatibility is mediated by the promoter-proximal region. https://doi.org/10.1101/2025.10.14.682013

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