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Development. 2019 Jan 25;146(12). pii: dev168179. doi: 10.1242/dev.168179.

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

Author information

1
Max-Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany dpapado2@ed.ac.uk tomancak@mpi-cbg.de.
2
Max-Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
3
Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 10691 Stockholm, Sweden.
4
Center for Molecular Medicine (CMM), Department of Clinical Neuroscience, Karolinska Institutet, 17176 Stockholm, Sweden.
5
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden.
6
Laboratory of Biomedical Optics, Swiss Federal Institute of Technology, 1015 Lausanne, Switzerland.
7
Center for Systems Biology Dresden, 01307 Dresden, Germany.

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.

KEYWORDS:

Auto-regulation; Fluorescence correlation spectroscopy; Hox genes; Protein noise; Transcription factors; Variability

PMID:
30642837
DOI:
10.1242/dev.168179
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Conflict of interest statement

Competing interestsThe authors declare no competing or financial interests.

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