ArticlePLoS genetics2018
Degenerate Pax2 and Senseless binding motifs improve detection of low-affinity sites required for enhancer specificity.
Article in PLoS genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- Gene regulatory networks: from correlative models to causal explanations.Nature reviews. Genetics · 2026Review
- Article
- The ALX4 dimer structure provides insight into how disease alleles impact function.Nature communications · 2025Article
- A suboptimal OCT4-SOX2 binding site facilitates the naïve-state specific function of a Klf4 enhancer.PloS one · 2024Article
- "Stripe" transcription factors provide accessibility to co-binding partners in mammalian genomes.Molecular cell · 2022Article
- Enhancers with cooperative Notch binding sites are more resistant to regulation by the Hairless co-repressor.PLoS genetics · 2021Article
- Androgen receptor positively regulates gonadotropin-releasing hormone receptor in pituitary gonadotropes.Molecular and cellular endocrinology · 2021Article
- Enhancer grammar in development, evolution, and disease: dependencies and interplay.Developmental cell · 2021Review
- Conserved Gsx2/Ind homeodomain monomer versus homodimer DNA binding defines regulatory outcomes in flies and mice.Genes & development · 2021Article
- Mechanisms Underlying Hox-Mediated Transcriptional Outcomes.Frontiers in cell and developmental biology · 2021Review
- A low affinityeLife · 2020Article
- Functional genomic approaches to elucidate the role of enhancers during development.Wiley interdisciplinary reviews. Systems biology and medicine · 2020Review
- Low-Affinity Binding Sites and the Transcription Factor Specificity Paradox in Eukaryotes.Annual review of cell and developmental biology · 2019Review
- The cis-regulatory logic underlying abdominal Hox-mediated repression versus activation of regulatory elements in Drosophila.Developmental biology · 2019Article
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Authors and funding
5 authors.
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Abstract
Cells use thousands of regulatory sequences to recruit transcription factors (TFs) and produce specific transcriptional outcomes. Since TFs bind degenerate DNA sequences, discriminating functional TF binding sites (TFBSs) from background sequences represents a significant challenge. Here, we show that a Drosophila regulatory element that activates Epidermal Growth Factor signaling requires overlapping, low-affinity TFBSs for competing TFs (Pax2 and Senseless) to ensure cell- and segment-specific activity. Testing available TF binding models for Pax2 and Senseless, however, revealed variable accuracy in predicting such low-affinity TFBSs. To better define parameters that increase accuracy, we developed a method that systematically selects subsets of TFBSs based on predicted affinity to generate hundreds of position-weight matrices (PWMs). Counterintuitively, we found that degenerate PWMs produced from datasets depleted of high-affinity sequences were more accurate in identifying both low- and high-affinity TFBSs for the Pax2 and Senseless TFs. Taken together, these findings reveal how TFBS arrangement can be constrained by competition rather than cooperativity and that degenerate models of TF binding preferences can improve identification of biologically relevant low affinity TFBSs.
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