ArticlePhilosophical transactions of the Royal Society of London. Series B, Biological sciences2013
Low-affinity transcription factor binding sites shape morphogen responses and enhancer evolution.
Article in Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 71 papers.
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Who cites it
71 citing papers in PubMed.
- Missense variants in human forkhead transcription factors reveal determinants of forkhead DNA bispecificity.Cell reports · 2025Article
- Emergence of activation or repression in transcriptional control under a fixed molecular context.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Runaway evolution of telomeres in ascomycetous yeasts was accompanied by the replacement of ancestral telomeric proteins.Nucleic acids research · 2025Article
- Bicoid-nucleosome competition sets a concentration threshold for transcription constrained by genome replication.Cell reports · 2025Article
- Missense variants in human forkhead transcription factors reveal determinants of forkhead DNA bispecificity.bioRxiv : the preprint server for biology · 2025Article
- Optimized DNA affinity purification sequencing determines relative binding affinity of transcription factors.Biology methods & protocols · 2025Article
- Optimization of the Irf8 +32-kb enhancer disrupts dendritic cell lineage segregation.Nature immunology · 2024Article
- A suboptimal OCT4-SOX2 binding site facilitates the naïve-state specific function of a Klf4 enhancer.PloS one · 2024Article
- Modulation of protein-DNA binding reveals mechanisms of spatiotemporal gene control in earlyeLife · 2023Article
- Optimisation of TP53 reporters by systematic dissection of synthetic TP53 response elements.Nucleic acids research · 2023Article
- KaScape: a sequencing-based method for global characterization of protein‒DNA binding affinity.Scientific reports · 2023Article
- Decoding enhancer complexity with machine learning and high-throughput discovery.Genome biology · 2023Review
- Transcriptional kinetic synergy: A complex landscape revealed by integrating modeling and synthetic biology.Cell systems · 2023Article
- Theme and variation in the evolution of insect sex determination.Journal of experimental zoology. Part B, Molecular and developmental evolution · 2023Review
- Hedgehog-mediated gut-taste neuron axis controls sweet perception in Drosophila.Nature communications · 2022Article
- On the incongruence of genotype-phenotype and fitness landscapes.PLoS computational biology · 2022Article
- Specificity of the Hox member Deformed is determined by transcription factor levels and binding site affinities.Nature communications · 2022Article
- The Non-continuum Nature of Eukaryotic Transcriptional Regulation.Advances in experimental medicine and biology · 2022Article
- Both Binding Strength and Evolutionary Accessibility Affect the Population Frequency of Transcription Factor Binding Sequences in Arabidopsis thaliana.Genome biology and evolution · 2021Article
- Androgen receptor positively regulates gonadotropin-releasing hormone receptor in pituitary gonadotropes.Molecular and cellular endocrinology · 2021Article
11 more citing papers are in PubMed but not listed here.
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2 authors.
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Abstract
In the era of functional genomics, the role of transcription factor (TF)-DNA binding affinity is of increasing interest: for example, it has recently been proposed that low-affinity genomic binding events, though frequent, are functionally irrelevant. Here, we investigate the role of binding site affinity in the transcriptional interpretation of Hedgehog (Hh) morphogen gradients. We noted that enhancers of several Hh-responsive Drosophila genes have low predicted affinity for Ci, the Gli family TF that transduces Hh signalling in the fly. Contrary to our initial hypothesis, improving the affinity of Ci/Gli sites in enhancers of dpp, wingless and stripe, by transplanting optimal sites from the patched gene, did not result in ectopic responses to Hh signalling. Instead, we found that these enhancers require low-affinity binding sites for normal activation in regions of relatively low signalling. When Ci/Gli sites in these enhancers were altered to improve their binding affinity, we observed patterning defects in the transcriptional response that are consistent with a switch from Ci-mediated activation to Ci-mediated repression. Synthetic transgenic reporters containing isolated Ci/Gli sites confirmed this finding in imaginal discs. We propose that the requirement for gene activation by Ci in the regions of low-to-moderate Hh signalling results in evolutionary pressure favouring weak binding sites in enhancers of certain Hh target genes.
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