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High Sensitivity Measurement of Transcription Factor-DNA Binding Affinities by Competitive Titration Using Fluorescence Microscopy
Published on: February 7, 2019
Transcription factor binding kinetics constrain noise suppression via negative feedback
Andreas Grönlund1, Per Lötstedt, Johan Elf
1Department for Cell and Molecular Biology, Science For Life Laboratory, Uppsala University, SE-751 24 Uppsala, Sweden.
Nature Communications
|May 16, 2013
Summary
Negative autoregulation uses transcription factors to stabilize gene expression. Optimal binding strength balances slow association kinetics, maximizing noise suppression and revealing binding site strength may not correlate with functional importance.
Area of Science:
- Molecular Biology
- Systems Biology
- Biophysics
Background:
- Negative autoregulation is a common gene expression mechanism to reduce fluctuations.
- Transcription factor binding to DNA is a slow process, limiting feedback speed and strength.
- Previous understanding suggested a direct correlation between binding site strength and regulatory function.
Purpose of the Study:
- To investigate the relationship between transcription factor binding kinetics and gene expression noise suppression.
- To determine if an optimal binding strength exists for maximizing noise reduction.
- To explore the implications of slow binding kinetics on transcription factor concentration and binding site strength.
Main Methods:
- Theoretical modeling of transcription factor-DNA interactions.
- Analysis of single-molecule imaging data on transcription factor binding dynamics.
- Mathematical derivation of noise suppression as a function of binding strength and association rate.
Main Results:
- A limited association rate necessitates an optimal transcription factor binding strength for maximal noise suppression.
- At this optimal strength, the binding site remains unoccupied for a fixed fraction of time, irrespective of transcription factor concentration.
- High-copy number transcription factors in Escherichia coli exhibit weak binding, consistent with theoretical predictions.
Conclusions:
- Gene expression noise can be maximally suppressed when transcription factor binding strength is optimized relative to association kinetics.
- The functional importance of a binding site may not be directly correlated with its binding strength.
- Findings challenge the assumption that stronger binding always equates to greater regulatory control in biological systems.
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