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Cooperative Binding of Transcription Factors is a Hallmark of Active Enhancers

Satyanarayan Rao, Kami Ahmad, View ORCID ProfileSrinivas Ramachandran
doi: https://doi.org/10.1101/2020.08.17.253146
Satyanarayan Rao
1Department of Biochemistry and Molecular Genetics, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue, North Seattle, WA 98109, USA
2RNA Bioscience Initiative, University of Colorado School of Medicine, Mail Stop: 8101, 12801 East 17th Ave. L-18-9102, Aurora, CO 80045
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Kami Ahmad
3Basic Sciences Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue, North Seattle, WA 98109, USA
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Srinivas Ramachandran
1Department of Biochemistry and Molecular Genetics, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue, North Seattle, WA 98109, USA
2RNA Bioscience Initiative, University of Colorado School of Medicine, Mail Stop: 8101, 12801 East 17th Ave. L-18-9102, Aurora, CO 80045
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  • ORCID record for Srinivas Ramachandran
  • For correspondence: srinivas.ramachandran@cuanschutz.edu
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Abstract

Enhancers harbor binding motifs that recruit transcription factors (TFs) for gene activation. While cooperative binding of TFs at enhancers is known to be critical for transcriptional activation of a handful of developmental enhancers, the extent TF cooperativity genome-wide is unknown. Here, we couple high-resolution nuclease footprinting with single-molecule methylation profiling to characterize TF cooperativity at active enhancers in the Drosophila genome. Enrichment of short MNase-protected DNA segments indicates that the majority of enhancers harbor two or more TF binding sites, and we uncover protected fragments that correspond to co-bound sites in thousands of enhancers. We integrate MNase-seq, methylation accessibility profiling, and CUT&RUN chromatin profiling as a comprehensive strategy to characterize co-binding of the Trithorax-like (TRL) DNA binding protein and multiple other TFs and identify states where an enhancer is bound by no TF, by either single factor, by multiple factors, or where binding sites are occluded by nucleosomes. From the analysis of co-binding, we find that cooperativity dominates TF binding in vivo at a majority of active enhancers. TF cooperativity can occur without apparent protein-protein interactions and provides a mechanism to effectively clear nucleosomes and promote enhancer function.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted August 18, 2020.
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Cooperative Binding of Transcription Factors is a Hallmark of Active Enhancers
Satyanarayan Rao, Kami Ahmad, Srinivas Ramachandran
bioRxiv 2020.08.17.253146; doi: https://doi.org/10.1101/2020.08.17.253146
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Cooperative Binding of Transcription Factors is a Hallmark of Active Enhancers
Satyanarayan Rao, Kami Ahmad, Srinivas Ramachandran
bioRxiv 2020.08.17.253146; doi: https://doi.org/10.1101/2020.08.17.253146

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