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Low Affinity Binding Site Clusters Confer Hox Specificity and Regulatory Robustness
Open accessAbstract
In animals, Hox transcription factors define regional identity in distinct anatomical domains. How Hox genes encode this specificity is a paradox, because different Hox proteins bind with high affinity in vitro to similar DNA sequences. Here, we demonstrate that the Hox protein Ultrabithorax (Ubx) in complex with its cofactor Extradenticle (Exd) bound specifically to clusters of very low affinity sites in enhancers of the shavenbaby gene of Drosophila. These low affinity sites conferred specificity for Ubx binding in vivo, but multiple clustered sites were required for robust expression when embryos developed in variable environments. Although most individual Ubx binding sites are not evolutionarily conserved, the overall enhancer architecture-clusters of low affinity binding sites-is maintained and required for enhancer function. Natural selection therefore works at the level of the enhancer, requiring a particular density of low affinity Ubx sites to confer both specific and robust expression.
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“Another means by which flexible enhancer grammar ensures robust gene expression control is through “suboptimal” TF binding motifs, which reinforce the requirement for TF cooperativity and create opportunities for fine-tuning enhancer activity levels [125–128].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [126]
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“Recent studies in Drosophila have uncovered an inverse relationship between the affinity of the binding site and its specificity for a given transcription factor (that is, low-affinity binding sites have the highest transcription factor specificity); moreover, clustered low-affinity sites contribute to the robustness…”
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“…regulation by HD proteins, recent evidence suggesting that clusters of low affinity sites also play important roles in gene regulation by HD proteins (Crocker et al. 2015) suggests that in silico searches using high-affinity sequences might miss many functionally relevant sites (see also below).”
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Background
Metadata
- Authors
- Crocker, J., Abe, N., Rinaldi, L., McGregor, A. P., Frankel, N., Wang, S., Alsawadi, A., Valenti, P., Plaza, S., Payre, F., Mann, R. S., & Stern, D. L.
- Affiliations
- Howard Hughes Medical Institute (US)
- Columbia University Irving Medical Center (US)
- Oxford Brookes University (GB)
- Consejo Nacional de Investigaciones Científicas y Técnicas (AR)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Mann, Richard S.
- Stern, David L.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-01
- Volume
- 160
- Issue
- 1-2
- Pages
- 191-203
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4449256
- OpenAlex
- W2002964220
- Cited by
- 363
- References
- 73
- Citations by year
- 2026: 16 · 2025: 22 · 2024: 36 · 2023: 30 · 2022: 39 · 2021: 31 · 2020: 34 · 2019: 30 · 2018: 37 · 2017: 35 · 2016: 31 · 2015: 22
- FWCI
- 12.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- Durham Research Online (Durham University) (submittedVersion, cc-by)
- CONICET Digital (CONICET) (submittedVersion, cc-by-nc-sa)
- Funders
- Agence Nationale de la Recherche (ANR-14-CE11-0010)
- National Institute of General Medical Sciences (R01GM054510, GM054510, R35GM118336)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- Hox transcription factors, Ultrabithorax, enhancer architecture, Drosophila embryogenesis, regional identity, transcriptional specificity, enhancer evolution
- MeSH terms
- Animals, Base Sequence, DNA-Binding Proteins, Drosophila melanogaster, Embryo, Nonmammalian, Enhancer Elements, Genetic, Gene Expression Regulation, Molecular Sequence Data, Protein Binding, Transcription Factors, Sequence Alignment, Homeodomain Proteins, Drosophila Proteins
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