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Control of Hox transcription factor concentration and cell-to-cell variability by an auto-regulatory switch
Open accessPreprint — published as 10.1242/dev.168179 · Paper page
Abstract
The variability in transcription factor concentration among cells is an important developmental determinant, yet how variability is controlled remains poorly understood. Studies of variability have focused predominantly on monitoring mRNA production noise. Little information exists about transcription factor protein variability, since this requires the use of quantitative methods with single-molecule sensitivity. Using Fluorescence Correlation Spectroscopy (FCS), we characterised the concentration and variability of 14 endogenously tagged TFs in live Drosophila imaginal discs. For the Hox TF Antennapedia we investigated whether protein variability results from random stochastic events or is developmentally regulated. We found that Antennapedia transitioned from low concentration/high variability early, to high concentration/low variability later, in development. FCS and temporally resolved genetic studies uncovered that Antp itself is necessary and sufficient to drive a developmental regulatory switch from auto-activation to auto-repression, thereby reducing variability. This switch is controlled by progressive changes in relative concentrations of preferentially activating and repressing Antennapedia isoforms, which bind chromatin with different affinities. Mathematical modelling demonstrated that the experimentally supported auto-regulatory circuit can explain the increase of Antennapedia concentration and suppression of variability over time.
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Global quantification of mammalian gene expression control
Schwanhäusser, B., Busse, D., Li, N., Dittmar, G., Schuchhardt, J., Wolf, J., Chen, W., & Selbach, M. (2011) · Nature · doi:10.1038/nature10098 · Cited by 6,566
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Metadata
- Authors
- Papadopoulos, D. K., Skouloudaki, K., Engstrom, Y., Terenius, L., Rigler, R., Zechner, C., Vukojevic, V., & Tomancak, P.
- Affiliations
- Institute of Genetics and Cancer (GB)
- Max Planck Institute of Molecular Cell Biology and Genetics (DE)
- Karolinska Institutet (SE)
- Center for Systems Biology Dresden (DE)
- Corresponding author
- Papadopoulos, Dimitrios K.
- ORCID
- Venue
- Development
- Publisher
- openRxiv
- Published
- 2017-03-14
- Volume
- 146
- Issue
- 12
- ISSN
- 0950-1991 (ISSN-L)
- PMC
- PMC6602345
- OpenAlex
- W2950674378
- Cited by
- 41
- References
- 1
- Citations by year
- 2026: 16 · 2024: 1 · 2023: 2 · 2022: 3 · 2021: 2 · 2020: 11 · 2019: 6
- FWCI
- 1.82
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Development (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- SDL (submittedVersion, cc-by)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- HighWire Press Open Archive (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- National Science Foundation
- Federation of European Biochemical Societies
- University of Edinburgh
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (138700)
- Karolinska Institutet
- Knut och Alice Wallenbergs Stiftelse
- Max-Planck-Gesellschaft
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- Hox transcription factors, Antennapedia, transcription factor concentration, cell-to-cell variability, auto-activation, developmental gene regulation, Drosophila imaginal discs, transcriptional noise, mathematical modeling of gene regulation
- MeSH terms
- Alleles, Animals, Binding Sites, Chromatin, Drosophila melanogaster, Enhancer Elements, Genetic, Female, Genes, Homeobox, Genotype, Homozygote, Male, Models, Biological, Models, Theoretical, Phenotype, Protein Binding, RNA, Messenger, Spectrometry, Fluorescence, Stochastic Processes, Transcription Factors, Homeodomain Proteins, Gene Expression Regulation, Developmental, Transgenes, Protein Isoforms, Drosophila Proteins, Antennapedia Homeodomain Protein, Imaginal Discs
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