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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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“affinity sites have been shown to be critical for Hox segment/regional specificity [16,17], which might be also the case for Hox tissue specificity.”
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“This is equivalent to computing the ratio of sufficiency test for the sub-tiles versus the whole tile.”
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“Homotypic clustering of multiple, non-overlapping low affinity binding sites adjacent to each other can serve regulatory roles by increasing local TF concentrations, either cooperatively ( 31 ) or non-cooperatively ( 32 ), to achieve phenotypic robustness ( 28 , 31 ).”
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The ALX4 dimer structure provides insight into how disease alleles impact function
Cain, B., Yuan, Z., Thoman, E., Kovall, R. A., & Gebelein, B. A. (2025) · Nature Communications · doi:10.1038/s41467-025-59728-9 · Cited by 3
“9) de novo motif analysis identi fi ed 6, 12, and 18 bp length enriched sequences in the ALX4 C&R datasets 30 . annotate-Peaks.pl from the Homer package was used to annotate the coordinator, dimer, monomer, and E-box sites within the ALX4 bound regions.”
Methods of massive parallel reporter assays for investigation of enhancers
Romanov, S. E., Kalashnikova, D. A., & Laktionov, P. P. (2021) · Vavilov Journal of Genetics and Breeding · doi:10.18699/vj21.038 · Cited by 3
Avetisyan, A. A., Glatt, Y., Cohen, M., Timerman, Y., Aspis, N., Nachman, A., Halachmi, N., Noon, E. P., & Salzberg, A. (2021) · eLife · doi:10.7554/elife.70833 · Cited by 3
Nanoscale nuclear environments, fine-scale 3D genome organization and transcription regulation
Li, J., & Pertsinidis, A. (2022) · Current Opinion in Systems Biology · doi:10.1016/j.coisb.2022.100436 · Cited by 3
Goluguri, R. R., Ghosh, C., Quintong, J., Sadqi, M., & Muñoz, V. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae790 · Cited by 3
“These imperfect motif clusters are known to increase local TF occupancy in vivo ( 44 ), and their removal from enhancers impairs cell fate stability during embryonic development ( 45 ,46 ).”
The regulatory function of dIno80 correlates with its DNA binding activity
Jain, S., Maini, J., Narang, A., Maiti, S., & Brahmachari, V. (2020) · Gene · doi:10.1016/j.gene.2020.144368 · Cited by 3
Molecular Characterization of HOXA2 and HOXA3 Binding Properties
Mallen, J., Kalsan, M., Zarrineh, P., Bridoux, L., Ahmad, S., & Bobola, N. (2021) · Journal of Developmental Biology · doi:10.3390/jdb9040055 · Cited by 3
Kittelmann, S., Buffry, A. D., Franke, F. A., Almudí, I., Yoth, M., Sabarís, G., Couso, J. P., Nunes, M. D. S., Frankel, N., Gómez-Skármeta, J. L., et al. (2017) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/219337 · Cited by 3
Self-citationGurska, D., Jentzsch, I. M. V., & Panfilio, K. A. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/427245 · Cited by 3
Infection-Genomics of COVID-19: Are Some Communities Resistant?Preprint
Kini, R. M., & Kundu, S. (2020) · Preprints.org · doi:10.20944/preprints202004.0310.v2 · Cited by 3
Hastings, R., Aditham, A. K., DelRosso, N. V., Suzuki, P., & Fordyce, P. M. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.11.13.566946 · Cited by 4
“Underscoring the importance of these interactions, low-affinity DNA sites are conserved and important for gene regulation 21,23,24 ; many enhancers are evolved for suboptimal affinities such that increasing affinity is pathogenic or disrupts specific and properly timed gene expression 9–14 .”
BackgroundWidespread low-affinity motifs enhance chromatin accessibility and regulatory potential in mESCsPreprint
Weilert, M., Brennan, K., Dalal, K., Krueger, S., Jiang, H., Martinez-Corral, R., & Zeitlinger, J. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.11.18.685822 · Cited by 3
“6,7 Mapping functional low-affinity motifs across the genome is however challenging.”
DNA–Protein Binding is Dominated by Short Anchoring Elements
Chen, H., Xu, Y., Ge, H., & Su, X. (2025) · Advanced Science · doi:10.1002/advs.202414823 · Cited by 2
Chemical Control of Genes: Synthetic Genome Readers and Gene Regulators
Ansari, A. Z., Mohammed, A., Achari, A., Danda, A., Philips, S. J., Deane, C. D., & Kandikonda, S. (2025) · Chemical Reviews · doi:10.1021/acs.chemrev.5c00112 · Cited by 2
Khan, S., Pradhan, S. J., Giraud, G., Bleicher, F., Paul, R., Merabet, S., & Shashidhara, L. S. (2023) · Journal of Molecular Evolution · doi:10.1007/s00239-023-10123-2 · Cited by 2
“However, previously reported low affinity binding sites such as those with TAAT motif (Galant et al. 2002; Walsh and Carroll 2007; Crocker et al. 2015; Loker et al. 2021) were not enriched in ChIP-pulled down sequences from either Drosophila and Apis (Prasad et al. 2016).”
BackgroundChromosomes come together to help mice distinguish odours
Spitz, F. (2019) · Nature · doi:10.1038/d41586-019-00010-6 · Cited by 2
Two distinct motifs for Zic-r.a drive specific gene expression in two cell lineages
Oda‐Ishii, I., Yu, D., & Satou, Y. (2021) · Development · doi:10.1242/dev.199538 · Cited by 2
MADS specificity : Unravelling the dual function of the MADS domain protein FRUITFULL
van Mourik, H. (2017) · doi:10.18174/421563 · Cited by 2
Poul, Y. L., Xin, Y., Ling, L., Mühling, B., Jaenichen, R., Hörl, D., Bunk, D., Harz, H., Leonhardt, H., Wang, Y., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.06.24.169748 · Cited by 2
“By contrast, other studies have quantified pattern elements of enhancer activity but with limited spatial resolution (Crocker et al., 2015; Crocker and Stern, 2017; Dufourt et al., 2018)).”
ResultA dual mechanism of enhancer activation by FOXA pioneer factors induces endodermal organ fatesPreprint
Geusz, R. J., Wang, A., Lam, D. K., Vinckier, N. K., Alysandratos, K., Roberts, D. A., Wang, J., Kefalopoulou, S., Qiu, Y., Chiou, J., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.08.28.263020 · Cited by 2
“Furthermore, studies in Drosophila and Ciona suggest that suboptimization of TF binding motifs could be a general principle by which to confer cell specificity to enhancers (Crocker et al., 2015; Farley et al., 2015).”
BackgroundVaishnav, E. D., de Boer, C. G., Yassour, M., Molinet, J., Fan, L., Adiconis, X., Thompson, D. A., Cubillos, F. A., Levin, J. Z., & Regev, A. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.02.17.430503 · Cited by 2
“Although gene regulatory networks often appear to be highly interconnected( 42 , 50 – 52 ), the sources of this regulatory complexity and how it changes with the turnover of regulatory mechanisms( 53 ) remain unclear.”
BackgroundJindal, G. A., Bantle, A. T., Solvason, J. J., Grudzien, J. L., D'Antonio-Chronowska, A., Lim, F., Le, S. H., Larsen, R. O., Klie, A., Frazer, K., et al. (2022) · bioRxiv · doi:10.1101/2022.05.27.493636 · Cited by 2
“The use of low-affinity sites is also important within enhancers activated by other transcription factors that act downstream of signaling pathways and pleiotropic factors (Crocker et al., 2015, 2016; Farley et al., 2015; Rowan et al., 2010; Tsai et al., 2017).”
BackgroundInfluentialSigalova, O. M., Forneris, M., Stojanovska, F., Zhao, B., Viales, R. R., Rabinowitz, A. H., Hammal, F., Ballester, B., Zaugg, J. B., & Furlong, E. E. M. (2025) · Genome Research · doi:10.1101/gr.279652.124 · Cited by 2
“This implies more complex mechanisms in the majority of cases, including the presence of cryptic low-affinity binding sites (Crocker et al. 2015; Kribelbauer et al. 2019), cooperative binding (Spitz and Furlong 2012; Jolma et al. 2015; Ibarra et al. 2020), and long-range interactions (Rao et al.…”
Rühle, J., Frömel, R., Bernal, A., Szu‐Tu, C., Bowness, J. S., & Velten, L. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.02.27.708495 · Cited by 2
Novel Antennapedia and Ultrabithorax trimeric complexes with TBP and Exd regulate transcription
Villarreal-Puente, A., Altamirano‐Torres, C., Jiménez-Mejía, G., Hernández-Bautista, C., Montalvo-Méndez, R. J., Vâzquez, M., Zurita, M., & Reséndez‐Pérez, D. (2024) · Hereditas · doi:10.1186/s41065-024-00327-x · Cited by 1
“4C and E), however, this result is coherent with the fact that Exd also interacts with Ubx [16].”
ResultWeilert, M., Brennan, K., Dalal, K., Krueger, S., Jiang, H., Martinez-Corral, R., & Zeitlinger, J. (2026) · Cell Genomics · doi:10.1016/j.xgen.2026.101339 · Cited by 6
“6,7 Mapping functional low-affinity motifs across the genome is challenging.”
Estimating DNA-Binding Specificities of Transcription Factors Using SELEX-Seq
Chen, P., Smaczniak, C., Haffner, J., Muiño, J. M., & Kaufmann, K. (2023) · Methods in molecular biology · doi:10.1007/978-1-0716-3354-0_10 · Cited by 1
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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