Intrinsic promoter responsiveness dictates sensitivity to transcriptional activation by enhancers
Year: 2026
Type: preprint
Abstract: Enhancers activate specific target promoters, but whether intrinsic enhancer-promoter compatibility contributes to this specificity is debated. Recent studies using different reporter assays have reached contradictory conclusions. We compare six reporter assay designs, identify confounders that bias compatibility measurements, and apply improved assays to test 25,000 enhancer-promoter pairs. Promoters differ in their responsiveness to enhancers (>100-fold versus 1.1-fold activation) while enhancers activate all promoters in a similar rank order. Promoter output scales with enhancer activity following a power law, with the exponent varying across promoters. Incorporating this exponent into the Activity-by-Contact model improves prediction of endogenous enhancer effects, explaining why certain active genes are insensitive to distal perturbations and "skipped" by enhancers. Responsiveness is modulated by transcription factor motifs in the core promoter. This work establishes responsiveness as an intrinsic promoter property that enables specific promoters to be highly activated in a landscape of broadly compatible enhancers, while others remain unaffected.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: National Science Foundation, Applebaum Foundation, Novo Nordisk, Novo Nordisk Fonden, National Institutes of Health, Stanford Bio-X, Stanford Research Computing Center, Stanford University, National Human Genome Research Institute, National Institute of Allergy and Infectious Diseases, National Institute of Neurological Disorders and Stroke
Awards: Defining and perturbing gene regulatory dynamics in the developing human heart to understand mechanisms of congenital heart defects, G2911450482, G3062824171, G4772171027, G5211151649, Graduate Research Fellowship Program (GRFP), G6661425536, Mapping, programming, and correcting gene regulatory sequences for Alagille Syndrome, Spatial multiomic mapping of gene function with CRISPRoff, Combinatorial Cell State Engineering, Defining and perturbing gene regulatory dynamics in the developing human brain, Vaccine and Infection Induced Immunity in the Young and Aged, Fast, powerful, scalable, usable, and distributable methods for multi-modal single cell analyses
OpenAlex ID: W7166375914
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