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Cited by 41Gene Regulatory Network AnalysisDevelopmental Biology and Gene RegulationGenomics and Chromatin Dynamics

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Control of Hox transcription factor concentration and cell-to-cell variability by an auto-regulatory switch

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Papadopoulos, Dimitrios K., Skouloudaki, Kassiani, Engström, Ylva, Terenius, Lars, Rigler, Rudolf, Zechner, Christoph, Vukojević, Vladana, Tomancak, Pavel·2019·Development
DOI 10.1242/dev.168179PMC PMC6602345

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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, as this requires the use of quantitative methods with single-molecule sensitivity. Using Fluorescence Correlation Spectroscopy (FCS), we have characterized 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 Antennapedia 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 modeling 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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Metadata

Authors
Papadopoulos, D. K., Skouloudaki, K., Engström, Y., Terenius, L., Rigler, R., Zechner, C., Vukojević, V., & Tomancak, P.
Affiliations
  • Institute of Genetics and Cancer (GB)
  • Max Planck Institute of Molecular Cell Biology and Genetics (DE)
  • Stockholm University (SE)
  • Karolinska Institutet (SE)
  • Center for Systems Biology Dresden (DE)
  • Max-Planck Institute of Molecular Cell Biology and Genetics 1 , 01307 Dresden , Germany
Corresponding author
Papadopoulos, Dimitrios K.
ORCID
Venue
Development
Publisher
The Company of Biologists
Published
2019-01-25
Volume
146
Issue
12
ISSN
  • 0950-1991 (ISSN-L)
  • 1477-9129
DOI
10.1242/dev.168179
PMC
PMC6602345
OpenAlex
W2950674378
Cited by
41
References
5
Citations by year
2026: 16 · 2024: 1 · 2023: 2 · 2022: 3 · 2021: 2 · 2020: 11 · 2019: 6
FWCI
1.81
Type
journal article
Language
en
Open access
Licence
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
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (PBBSP-138700)
  • Federation of European Biochemical Societies
  • Max-Planck-Gesellschaft
  • University of Edinburgh
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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