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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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Peng, P.-C., Khoueiry, P., Girardot, C., Reddington, J. P., Garfield, D. A., Furlong, E. E. M., & Sinha, S. (2019) · Genome Biology and Evolution · doi:10.1093/gbe/evz103 · Cited by 19
Functional regulatory evolution outside of the minimal even-skipped stripe 2 enhancer
Crocker, J., & Stern, D. L. (2017) · Development · doi:10.1242/dev.149427 · Cited by 16
Self-citationLighting up the central dogma for predictive developmental biology
García, H. G., Berrocal, A., Kim, Y. J., Martini, G. D., & Zhao, J. (2019) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2019.10.010 · Cited by 19
Zandvakili, A., Campbell, I., Gutzwiller, L. M., Weirauch, M. T., & Gebelein, B. A. (2018) · PLoS Genetics · doi:10.1371/journal.pgen.1007289 · Cited by 17
Specificity landscapes unmask submaximal binding site preferences of transcription factors
Bhimsaria, D., Rodríguez‐Martínez, J. A., Pan, J., Roston, D., Korkmaz, E. N., Cui, Q., Ramanathan, P., & Ansari, A. Z. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1811431115 · Cited by 17
Hastings, R., Aditham, A. K., DelRosso, N. V., Suzuki, P., & Fordyce, P. M. (2025) · Nature Communications · doi:10.1038/s41467-024-55672-2 · Cited by 17
“7), converted intensities to DNA concentrations based on orthogonal measurements using a DeNovix instrument, and then fi t concentration-dependent binding curves as described below.”
Datta, R. R., & Rister, J. (2022) · BioEssays · doi:10.1002/bies.202100191 · Cited by 17
“slightly different high affinity dual function Otd activator/Dve repressor K50motif in rhodopsins to generate restricted expression patterns, that is, the switch from high affinity binding of one transcription factor type to high affinity binding of another transcription factor type, differs from how Hox transcription…”
BackgroundCompeting constraints shape the nonequilibrium limits of cellular decision-making
Lammers, N. C., Flamholz, A. I., & García, H. G. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2211203120 · Cited by 16
Modeling and designing enhancers by introducing and harnessing transcription factor binding units
Li, J., Zhang, P., Xi, X., Liu, L., Wei, L., & Wang, X. (2025) · Nature Communications · doi:10.1038/s41467-025-56749-2 · Cited by 16
Yamamoto, S., Uchida, Y., Ohtani, T., Nozaki, E., Yin, C., Gotoh, Y., Yakushiji‐Kaminatsui, N., Higashiyama, T., Suzuki, T., Takemoto, T., et al. (2019) · Development Growth & Differentiation · doi:10.1111/dgd.12601 · Cited by 15
“In addition, the presence of the co- factors that modulate transcriptional activity of Drosophila HOX was reported (reviewed in Zandvakili & Gebelein, 2016).”
BackgroundLazar, J. E., Stehling-Sun, S., Nandakumar, V., Wang, H., Chee, D. R., Howard, N. P., Acosta, R., Dunn, D., Diegel, M., Neri, F. J., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107676 · Cited by 14
A fine kinetic balance of interactions directs transcription factor hubs to genesPreprint
Fallacaro, S., Mukherjee, A., Ratchasanmuang, P., Zinski, J. M., Haloush, Y. I., Shankta, K., & Mir, M. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.04.16.589811 · Cited by 15
“Although this redistribution is correlated with GAF binding and an increase in accessibility in ΔZLD embryos, tra nscription is further enhanced by the recruitment of ZF5.”
BackgroundTranscriptional cooperation of PBX1 and PAX6 in adult neural progenitor cells
Hau, A., Mommaerts, E., Laub, V., Müller, T., Dittmar, G. A. G., & Schulte, D. (2021) · Scientific Reports · doi:10.1038/s41598-021-99968-5 · Cited by 15
Papadopoulos, D. K., Krmpot, A. J., Nikolić, S. N., Krautz, R., Terenius, L. Y., Tomančák, P., Rigler, R. W., Gehring, W. J., & Vukojević, V. B. (2015) · Mechanisms of Development · doi:10.1016/j.mod.2015.09.004 · Cited by 15
“…of Hox transcription factors is just starting to be explored and has recently been characterized in the context of Ubx–Exd binding on enhancers of the shavenbaby (svb) gene, where clustered, low-affinity binding of Ubx–Exd complexes are required for robustness of expression (Crocker et al., 2015).”
Regulatory sharing between estrogen receptor α bound enhancers
Carleton, J. B., Ginley-Hidinger, M., Berrett, K. C., Layer, R. M., Quinlan, A. R., & Gertz, J. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa454 · Cited by 15
“Previous studies have found that multiple suboptimal TF binding motifs can drive expression of reporters in Ciona and Drosophila (Crocker et al., 2015; Farley et al., 2016).”
BackgroundContext-dependent HOX transcription factor function in health and disease
Bondos, S. E., Mendes, G. G., & Jons, A. (2020) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2020.05.003 · Cited by 15
Ryan, G. E., Bohaczuk, S. C., Cassin, J., Witham, E. A., Shojaei, S., Ho, E. V., Thackray, V. G., & Mellon, P. L. (2021) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2021.111286 · Cited by 16
FOXL2 and FOXA1 cooperatively assemble on the TP53 promoter in alternative dimer configurations
Choi, Y., Luo, Y., Lee, S., Jin, H., Yoon, H., Hahn, Y., Bae, J., & Lee, H. H. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac673 · Cited by 15
SELEX-Seq: A Method to Determine DNA Binding Specificities of Plant Transcription Factors
Smaczniak, C., Angenent, G. C., & Kaufmann, K. (2017) · Methods in molecular biology · doi:10.1007/978-1-4939-7125-1_6 · Cited by 15
Transcription factor interactions explain the context-dependent activity of CRX binding sites
Loell, K., Friedman, R. Z., Myers, C. A., Corbo, J. C., Cohen, B. A., & White, M. A. (2024) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1011802 · Cited by 17
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Gurská, D., Jentzsch, I. M. V., & Panfilio, K. A. (2020) · Communications Biology · doi:10.1038/s42003-020-01250-3 · Cited by 14
Developmental phenomics suggests that H3K4 monomethylation confers multi-level phenotypic robustness
Gándara, L., Tsai, A., Ekelöf, M., Galupa, R., Noon, E. P., Alexandrov, T., & Crocker, J. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111832 · Cited by 14
Self-citationBlassberg, R. A., Patel, H., Watson, T., Gouti, M., Metzis, V., Delàs, M. J., & Briscoe, J. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.12.29.424684 · Cited by 14
“…progenitors and CEpiLCs As cell-type specific TF binding at low affinity sites is associated with cooperative co-factor binding (Slattery et al., 2011) (Crocker et al., 2015), we reasoned that SOX2 occupancy at constitutively accessible sites might require additional cell-state specific co-factors.”
BackgroundMutational scans reveal differential evolvability of Drosophila promoters and enhancers
Li, X., Fuqua, T., van Breugel, M. E., & Crocker, J. (2023) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2022.0054 · Cited by 12
Self-citationRobust and efficient gene regulation through localized nuclear microenvironments
Tsai, A., Galupa, R., & Crocker, J. (2020) · Development · doi:10.1242/dev.161430 · Cited by 12
Self-citationReformulating nonequilibrium steady states and generalized Hopfield discrimination
Çetiner, U., & Gunawardena, J. (2022) · Physical review. E · doi:10.1103/physreve.106.064128 · Cited by 13
“This could be a particularly serious omission in biology, where functionality can arise from many small contributions [42].”
BackgroundDatta, V., Siddharthan, R., & Krishna, S. (2018) · PLoS ONE · doi:10.1371/journal.pone.0199771 · Cited by 13
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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