The words of the regulatory code are arranged in a variable manner in highly conserved enhancers
Open accessAbstract
The cis-regulatory regions of many developmental regulators and transcription factors are believed to be highly conserved in the genomes of vertebrate species, suggesting specific regulatory mechanisms for these gene classes. We functionally characterized five notochord enhancers, whose sequence is highly conserved, and systematically mutated two of them. Two subregions were identified to be essential for expression in the notochord of the zebrafish embryo. Synthetic enhancers containing the two essential regions in front of a TATA-box drive expression in the notochord while concatemerization of the subregions alone is not sufficient, indicating that the combination of the two sequence elements is required for notochord expression. Both regions are present in the five functionally characterized notochord enhancers. However, the position, the distance and relative orientation of the two sequence motifs can vary substantially within the enhancer sequences. This suggests that the regulatory grammar itself does not dictate the high evolutionary conservation between these orthologous cis-regulatory sequences. Rather, it represents a less well-conserved layer of sequence organization within these sequences.
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Enhancers consistent with the billboard model are likely also widespread in vertebrate genomes.
“Enhancers consistent with the billboard model are likely also widespread in vertebrate genomes [55, 93].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [93]
In “Highly conserved non-coding sequences and transcriptional regulation” (page unavailable), the paper calls many enhancers loose, variable assemblies of binding sites and identifies that structure as the billboard model. It also finds billboard-like organization in five zebrafish notochord enhancers. Those examples support the possibility, but the paper does not establish how widespread billboard-like enhancers are across vertebrate genomes. (LLM, conf=0.83)
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“The data therefore show that promoter activities were predominantly a function of the type and quantity of constituent TFREs, and constructed sequences functioned as ‘billboard promoters’, where the relative organization of composite TF binding sites had minimal influence on promoter activity (24,59).”
BackgroundBrachyury, Foxa2 and the cis-Regulatory Origins of the Notochord
José‐Edwards, D. S., Oda‐Ishii, I., Kugler, J. E., Passamaneck, Y. J., Katikala, L., Nibu, Y., & Gregorio, A. D. (2015) · PLoS Genetics · doi:10.1371/journal.pgen.1005730 · Cited by 42 · see citing works
“Foxa2 sites are required in notochord CRMs from zebrafish and mice [46,54], although they are rarely sufficient to initiate expression when in single copy, and often necessitate additional sequences [46,58,61] whose identity appears to be lineage-specific (Fig 4A and 4C).”
BackgroundCis-regulation and chromosomal rearrangement of the fgf8 locus after the teleost/tetrapod split
Komisarczuk, A. Z., Kawakami, K., & Becker, T. S. (2009) · Developmental Biology · doi:10.1016/j.ydbio.2009.09.029 · Cited by 41 · see citing works
Ultraconserved Elements: Analyses of Dosage Sensitivity, Motifs and Boundaries
Chiang, C. W. K., Derti, A., Schwartz, D., Chou, M. F., Hirschhorn, J. N., & Wu, C.-T. (2008) · Genetics · doi:10.1534/genetics.108.096537 · Cited by 37 · see citing works
Crocker, J., Ilsley, G. R., & Stern, D. L. (2016) · Nature Genetics · doi:10.1038/ng.3509 · Cited by 35 · see citing works
“These results suggest that enhancers can act as simple input-output devices, integrating total activation and repression across the enhancer, which is consistent with a growing number of studies 9,24,47–51 , 53 .”
ResultLiu, F., & Posakony, J. W. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002796 · Cited by 33 · see citing works
A Fully Synthetic Transcriptional Platform for a Multicellular Eukaryote
Crocker, J., Tsai, A., & Stern, D. L. (2017) · Cell Reports · doi:10.1016/j.celrep.2016.12.025 · Cited by 30 · see citing works
Computational analysis and characterization of UCE-like elements (ULEs) in plant genomesPreprint
Kritsas, K., Wuest, S. E., Hupalo, D., Kern, A. D., Wicker, T., & Grossniklaus, U. (2012) · Genome Research · doi:10.1101/gr.129346.111 · Cited by 32 · see citing works
“…is not sufficient to explain their high conservation, because all protein–DNA, DNA–DNA, or DNA–RNA interactions known to date tolerate significant sequence divergence without affecting their functions (Ludwig et al. 2000, 2005; Romano and Wray 2003; Poulin et al. 2005; Rastegar et al. 2008).”
BackgroundGregorio, A. D. (2020) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2020.01.002 · Cited by 31 · see citing works
Zhang, G., Ferg, M., Lübke, L., Takamiya, M., Beil, T., Gourain, V., Diotel, N., Strähle, U., & Rastegar, S. (2020) · Stem Cells · doi:10.1002/stem.3182 · Cited by 30 · see citing works
Self-citationNavrátilová, P., Fredman, D., Lenhard, B., & Becker, T. S. (2009) · Molecular Genetics and Genomics · doi:10.1007/s00438-009-0503-1 · Cited by 27 · see citing works
“Moreover, Rastegar et al. (2008) showed that rather Xexible arrangements of cis-regulatory modules can be embedded within regions of high sequence conservation and that deciphering the regulatory code requires functional analysis beyond simple sequence alignment.”
BackgroundUsing synthetic biology to study gene regulatory evolution
Crocker, J., & Ilsley, G. R. (2017) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2017.09.001 · Cited by 23 · see citing works
Enhancers display constrained sequence flexibility and context-specific modulation of motif functionPreprint
Reiter, F., de Almeida, B. P., & Stark, A. (2023) · Genome Research · doi:10.1101/gr.277246.122 · Cited by 24 · see citing works
Flexibility of transcription factor target site position in conserved cis-regulatory modules
Cameron, R. A., & Davidson, E. H. (2009) · Developmental Biology · doi:10.1016/j.ydbio.2009.09.018 · Cited by 24 · see citing works
“Outside of the dipterans comparisons of orthologous CRMs have tended to focus on non-coding sequences a priori chosen for study because of their remarkable conservation, often extending from fish to mammals (Siepel et al., 2005; Vavouri et al., 2007; Elgar and Vavouri, 2008; Rastegar et al., 2008; Wang et al., 2009; P…”
InfluentialSparkling Insights into Enhancer Structure, Function, and Evolution
Evans, N. C., Swanson, C. I., & Barolo, S. (2012) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/b978-0-12-386499-4.00004-5 · Cited by 20 · see citing works
Cis-regulatory characterization of sequence conservation surrounding the Hox4 genes
Punnamoottil, B., Herrmann, C., Pascual‐Anaya, J., D’Aniello, S., García‐Fernàndez, J., Akalin, A., Becker, T. S., & Rinkwitz, S. (2010) · Developmental Biology · doi:10.1016/j.ydbio.2010.01.035 · Cited by 20 · see citing works
“Further, cis-regulatory sequences often interact with each other to generate complete cis-regulatory modules as recently demonstrated for notochord-specific enhancers of the ctgf and sox9a genes (Rastegar et al., 2008).”
The architecture of binding cooperativity between densely bound transcription factors
Lupo, O., Kumar, D. K., Livne, R., Chappleboim, M., Levy, I., & Barkai, N. (2023) · Cell Systems · doi:10.1016/j.cels.2023.06.010 · Cited by 19 · see citing works
Alassaf, M., Daykin, E. C., Mathiaparanam, J., & Wolman, M. A. (2019) · eLife · doi:10.7554/elife.47061 · Cited by 19 · see citing works
“As a control for fluorescent cell sorting and detection of pappaa by RT-PCR, we performed RT-PCR for pappaa on fluorescently sorted motor neurons from five dpf Tg(mnx1:GFP) larvae (Rastegar et al., 2008), and confirmed pappaa expression by motor neurons (Figure 2C).”
MethodFunctional 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 · see citing works
Jana, T., Brodsky, S., Manadre, W., Vidavski, M., Valinsky, G., Mindel, V., Ilan, G., Carmi, M., Jonas, F., & Barkai, N. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae846 · Cited by 15 · see citing works
Gene transcription in the zebrafish embryo: regulators and networks
Ferg, M., Armant, O., Yang, L., Dickmeis, T., Rastegar, S., & Strähle, U. (2013) · Briefings in Functional Genomics · doi:10.1093/bfgp/elt044 · Cited by 15 · see citing works
“the five enhancers in an almost random fashion, suggesting that the conservation of the sequence is only indirectly linked to binding of TFs [83].”
BackgroundSelf-citationA long-range flexible billboard model of gene activation
Vockley, C. M., McDowell, I. C., D'Ippolito, A. M., & Reddy, T. E. (2017) · Transcription · doi:10.1080/21541264.2017.1317694 · Cited by 14 · see citing works
Alten, L., Schuster-Gossler, K., Eichenlaub, M., Wittbrodt, B., Wittbrodt, J., & Gossler, A. (2012) · PLoS ONE · doi:10.1371/journal.pone.0047785 · Cited by 12 · see citing works
“A major role of FOXA2 was suggested by loss of Noto expression in embryos lacking FOXA2 [11,12], as well as the presence of FOXA2 binding sites in the region 10 kb upstream the putative start site of Noto transcription and in the first intron, and a pivotal role of FOXA2 binding sites for the function of other notocho…”
BackgroundResultInfluentialPrinz, R., Bücher, P., Kun, Á., Paredes, O., Aragno, A., Shelby, C. L., Gumbel, M., Fimmel, E., & Strüngmann, L. (2025) · Biosystems · doi:10.1016/j.biosystems.2025.105515 · Cited by 9 · see citing works
From sequence to consequence: Deciphering the complex cis-regulatory landscape
Dsilva, G. J., & Galande, S. (2024) · Journal of Biosciences · doi:10.1007/s12038-024-00431-0 · Cited by 8 · see citing works
“2007; Rastegar et al .”
Spirov, A. V., & Myasnikova, E. M. (2018) · ICT Express · doi:10.1016/j.icte.2018.10.008 · Cited by 7 · see citing works
Evaluation of cis-regulatory function in zebrafish
Pashos, E. E., Kague, É., & Fisher, S. (2008) · Briefings in Functional Genomics and Proteomics · doi:10.1093/bfgp/eln045 · Cited by 7 · see citing works
“One recent study [59] identified five enhancers associated with four zebrafish genes expressed in the midline.”
BackgroundZhang, G., Ferg, M., Lübke, L., Takamiya, M., Beil, T., Gourain, V., Diotel, N., Strähle, U., & Rastegar, S. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/787804 · Cited by 5 · see citing works
Self-citationMaguire, J. E., Pandey, A., Wu, Y., & Gregorio, A. D. (2018) · Advances in experimental medicine and biology · doi:10.1007/978-981-10-7545-2_8 · Cited by 4 · see citing works
Sipani, R., & Joshi, R. (2022) · Genetics · doi:10.1093/genetics/iyac101 · Cited by 3 · see citing works
Higher-order chromatin structure and gene regulation
Nakai, K., & Vandenbon, A. (2023) · Elsevier eBooks · doi:10.1016/b978-0-12-823931-5.00022-0 · Cited by 3 · see citing works
Large-Scale Gene Regulatory Motif Discovery with NestedMICA
Piipari, M., Down, T. A., & Hubbard, T. (2011) · Science, engineering, and biology informatics · doi:10.1142/9789814327732_0001 · Cited by 2 · see citing works
The Zebrafish as Model for Deciphering the Regulatory Architecture of Vertebrate Genomes
Rastegar, S., & Strähle, U. (2016) · Advances in genetics · doi:10.1016/bs.adgen.2016.04.003 · Cited by 2 · see citing works
Self-citationChen, J., Takamiya, M., Hendriks, A., Beil, T., Várnai, C., Diotel, N., & Rastegar, S. (2025) · FEBS Journal · doi:10.1111/febs.70345 · Cited by 1 · see citing works
“Additionally, each CRE was tested in combination with three different promoters: the ctgf promoter [41], the zebrafish synthetic promoter (zsp) [42], and the mdka intrinsic promoter (mdkaPR, this study).”
Self-citationThe combinatorial binding syntax of transcription factors in forebrain-specific enhancers
Batool, F., Shireen, H., Malik, M. F., Abrar, M. M., & Abbasi, A. A. (2025) · Biology Open · doi:10.1242/bio.061751 · Cited by 1 · see citing works
“These include co-binding of TFs to specific DNA sequences (Zanconato et al., 2015), the spacing between individual TF binding motifs (Rastegar et al., 2008), the presence of numerous heterotypically cooperative and homotypically clustered motifs (Georgakopoulos-Soares et al., 2023), TF-DNA binding…”
Literature Review and Commentary
Begemann, G. (2008) · Zebrafish · doi:10.1089/zeb.2008.9985 · Cited by 1 · see citing works
Article Rapid Evolutionary Rewiring of a Structurally Constrained Eye Enhancer
Swanson, C. I., Schwimmer, D. B., & Barolo, S. (2011)
Quantifying Eukaryotic Gene Regulation in Hormone Response and Disease.
Vockley, C. M. (2016) · DukeSpace (Duke University)
Fuzzy Linguistic Modeling of the Regulation of Drosophila Segmentation Genes
Makashov, A., Myasnikova, E. M., & Spirov, A. V. (2021) · BIOPHYSICS · doi:10.1134/s0006350921010073
Recent Papers on Zebrafish and Other Aquarium Fish Models
(2008) · Zebrafish · doi:10.1089/zeb.2008.9987
cis-Regulation in the Mammalian Rod Photoreceptor
Kwasnieski, J. C. (2014) · Open Scholarship Institutional Repository (Washington University in St. Louis) · doi:10.7936/k7r20zc8
“Sequence features such as the number or affinity of a TFBS, can impact the control of gene expression (Yuh et al. 2001; Arnosti 2003; Rastegar et al. 2008) but it is not clear which patterns are important for gene activation.”
Background
- Authors
- Rastegar, S., Hess, I., Dickmeis, T., Nicod, J. C., Ertzer, R., Hadzhiev, Y., Thies, W.-G., Scherer, G., & Strähle, U.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- University of Freiburg (DE)
- Corresponding author
- Rastegar, Sepand
- Strähle, Uwe
- Venue
- Developmental Biology
- Publisher
- Elsevier BV
- Published
- 2008-06
- Volume
- 318
- Issue
- 2
- Pages
- 366-377
- ISSN
- 0012-1606 (ISSN-L)
- OpenAlex
- W1982649864
- Cited by
- 56
- References
- 81
- Citations by year
- 2025: 3 · 2024: 2 · 2023: 3 · 2022: 1 · 2021: 3 · 2020: 3 · 2019: 2 · 2018: 4 · 2017: 5 · 2016: 3 · 2015: 1 · 2014: 3 · 2013: 2 · 2012: 4
- FWCI
- 2.32
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- other-oa
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1908 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Developmental Biology (publishedVersion, other-oa)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- European Commission
- Deutsche Forschungsgemeinschaft
- Institut National de la Santé et de la Recherche Médicale
- Centre National de la Recherche Scientifique
- 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 › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Keywords
- cis-regulatory elements, enhancers, sequence conservation, synthetic enhancers, TATA box, zebrafish, developmental gene regulation, enhancer mutations
- MeSH terms
- Animals, Base Sequence, DNA Mutational Analysis, Enhancer Elements, Genetic, Humans, Notochord, Promoter Regions, Genetic, Zebrafish, Sequence Alignment, Conserved Sequence, Gene Expression Regulation, Developmental, HMGB Proteins, Zebrafish Proteins, Regulatory Elements, Transcriptional, Forkhead Transcription Factors, SOX9 Transcription Factor
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