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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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“Accordingly, binding site clusters, in particular 5 those composed of binding sites for the same transcription factor (homotypic clusters) or of low-affinity 6 sites, have received increasing attention with several functionally important examples identified to date 7 (Crocker et al. (2015); Kribelbauer et al. (2019);…”
BackgroundInfluentialRewriting regulatory DNA to dissect and reprogram gene expression
Martyn, G. E., Montgomery, M. T., Jones, H., Guo, K., Doughty, B. R., Linder, J., Bisht, D., Xia, F., Cai, X. S., Chen, Z., et al. (2023) · Cell · doi:10.1016/j.cell.2025.03.034 · Cited by 59
Cell-type-specific Hox regulatory strategies orchestrate tissue identity
Loker, R., Sanner, J. E., & Mann, R. S. (2021) · Current Biology · doi:10.1016/j.cub.2021.07.030 · Cited by 46
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Autoregulation of RCO by Low-Affinity Binding Modulates Cytokinin Action and Shapes Leaf Diversity
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“Conclusions Previous studies demonstrated that low-affinity transcription factor binding sites play a crucial role in activating developmental genes, thereby ensuring developmental robustness and precise patterns of tissue development [14, 40, 41].”
BackgroundTranscriptional Regulation and Implications for Controlling Hox Gene Expression
Afzal, Z., & Krumlauf, R. K. (2022) · Journal of Developmental Biology · doi:10.3390/jdb10010004 · Cited by 51
“Precise regulatory outputs from enhancers do not require that upstream factors have highly restricted domains of expression and can arise through the cumulative integration of weak, imprecise or wide-spread inputs by TFs [66,67].”
BackgroundDecoding enhancer complexity with machine learning and high-throughput discovery
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“These include through enhancer redundancy [142–144], the need for multiple TFs to bind together [137, 138], and the transmission of genetic signals through different layers of regulatory information [145].”
BackgroundTranscription factors perform a 2-step search of the nucleus
Staller, M. V. (2022) · Genetics · doi:10.1093/genetics/iyac111 · Cited by 52
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“found two CRMs from the shavenbaby (svb) locus that are activated in the abdomen by either Ubx/Exd or Abd-A/Exd complexes via low affinity sites [54].”
BackgroundTranscriptional Enhancers in Drosophila
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“tent with the idea that HOXA1 binding is stabilized through cooperative interactions with TALE proteins, and thus multiple sites could add robustness to HOXA1 binding (Berman et al. 2002; Crocker et al. 2015; Farley et al. 2015).”
BackgroundNatural variation in stochastic photoreceptor specification and color preference in Drosophila
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Cooperative assembly confers regulatory specificity and long-term genetic circuit stability
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TFBSshape: an expanded motif database for DNA shape features of transcription factor binding sites
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“In some cases, TFs recognize low-affinity binding sites with less pronounced sequence motifs (19,20) or tend to bind to DNA even in the absence of the sequence motif both in vitro (21) and in vivo (22).”
BackgroundLow-affinity SPL binding sites contribute to subgenome expression divergence in allohexaploid wheat
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“These results suggest the binding affinities are related to the motif sequences with which they preferentially associate (Crocker et al., 2015), although the binding preferences are also dependent on the chromatin accessibilities around the binding regions.”
BackgroundInterpreting cis-regulatory mechanisms from genomic deep neural networks using surrogate models
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Hox genes, evo-devo, and the case of the ftz gene
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“many Hox proteins, increasing their DNA-binding specificity in vitro and in vivo (Chan et al. 1994; Johnson et al. 1995; Chan and Mann 1996; Zhao et al. 1996; Crocker et al. 2015).”
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“Our findings are in great agreement with previous small-scale studies of TF paralogs, such as the Hox factors in Drosophila (Noro et al. 2011; Slattery et al. 2011; Crocker et al. 2015) and the POU homeodomain factors in mammals (Ferraris et al. 2011).”
BackgroundResultInfluentialIntrinsic DNA Shape Accounts for Affinity Differences between Hox-Cofactor Binding Sites
Zeiske, T., Baburajendran, N., Kaczynska, A., Brasch, J., Palmer, A. G. I., Shapiro, L. S., Honig, B. H., & Mann, R. S. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.07.100 · Cited by 39
“, the ability of closely related TF family members to selectively bind specific DNA sequences (Crocker et al., 2015).”
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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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