Systematic analysis of low-affinity transcription factor binding site clusters in vitro and in vivo establishes their functional relevance

Amir Shahein, Maria López-Malo, Ivan Istomin, Evan J. Olson, Shiyu Cheng and Sebastian J. Maerkl ()
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Amir Shahein: Institute of Bioengineering, School of Engineering, École Polytechnique Fédérale de Lausanne
Maria López-Malo: Institute of Bioengineering, School of Engineering, École Polytechnique Fédérale de Lausanne
Ivan Istomin: Institute of Bioengineering, School of Engineering, École Polytechnique Fédérale de Lausanne
Evan J. Olson: Institute of Bioengineering, School of Engineering, École Polytechnique Fédérale de Lausanne
Shiyu Cheng: Institute of Bioengineering, School of Engineering, École Polytechnique Fédérale de Lausanne
Sebastian J. Maerkl: Institute of Bioengineering, School of Engineering, École Polytechnique Fédérale de Lausanne

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Binding to binding site clusters has yet to be characterized in depth, and the functional relevance of low-affinity clusters remains uncertain. We characterized transcription factor binding to low-affinity clusters in vitro and found that transcription factors can bind concurrently to overlapping sites, challenging the notion of binding exclusivity. Furthermore, small clusters with binding sites an order of magnitude lower in affinity give rise to high mean occupancies at physiologically-relevant transcription factor concentrations. To assess whether the observed in vitro occupancies translate to transcriptional activation in vivo, we tested low-affinity binding site clusters in a synthetic and native gene regulatory network in S. cerevisiae. In both systems, clusters of low-affinity binding sites generated transcriptional output comparable to single or even multiple consensus sites. This systematic characterization demonstrates that clusters of low-affinity binding sites achieve substantial occupancies, and that this occupancy can drive expression in eukaryotic promoters.

Date: 2022
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DOI: 10.1038/s41467-022-32971-0

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