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Single position substitution of hairpin pyrrole-imidazole polyamides imparts distinct DNA-binding profiles across the human genome

Finn, Paul B. and Bhimsaria, Devesh and Ali, Asfa and Eguchi, Asuka and Ansari, Aseem Z. and Dervan, Peter B. (2020) Single position substitution of hairpin pyrrole-imidazole polyamides imparts distinct DNA-binding profiles across the human genome. . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20200818-152604358

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Abstract

Regulating desired loci in the genome with sequence-specific DNA-binding molecules is a major goal for the development of precision medicine. Pyrrole–imidazole (Py–Im) polyamides are synthetic molecules that can be rationally designed to target specific DNA sequences to both disrupt and recruit transcriptional machinery. While in vitro binding has been extensively studied, in vivo effects are often difficult to predict using current models of DNA binding. Determining the impact of genomic architecture and the local chromatin landscape on polyamide-DNA sequence specificity remains an unresolved question that impedes their effective deployment in vivo. In this report we identified polyamide–DNA interaction sites across the entire genome, by covalently crosslinking and capturing these events in the nuclei of human LNCaP cells. This method, termed COSMIC-seq, confirms the ability of hairpin-polyamides, with similar architectures but differing at a single ring position, to retain in vitro specificities and display distinct genome-wide binding profiles. These results underpin the development of Py-Im polyamides as DNA-targeting molecules that mediate their regulatory or remedial functions at desired genomic loci.


Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/2020.08.13.249730DOIDiscussion Paper
ORCID:
AuthorORCID
Finn, Paul B.0000-0002-1253-1314
Bhimsaria, Devesh0000-0001-8413-3801
Ali, Asfa0000-0001-8680-6184
Eguchi, Asuka0000-0003-3010-0275
Ansari, Aseem Z.0000-0003-1432-4498
Dervan, Peter B.0000-0001-8852-7306
Additional Information: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. Posted August 14, 2020. We thank Laura Vanderploeg for help with the artwork and Mackenzie C. Spurgat for preliminary CSI experiments. Sequencing was performed at the Millard and Muriel Jacobs Genetics and Genomics Laboratory at California Institute of Technology.
Group:Millard and Muriel Jacobs Genetics and Genomics Laboratory
Record Number:CaltechAUTHORS:20200818-152604358
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200818-152604358
Official Citation:Single position substitution of hairpin pyrrole-imidazole polyamides imparts distinct DNA-binding profiles across the human genome. Paul B. Finn, Devesh Bhimsaria, Asfa Ali, Asuka Eguchi, Aseem Z. Ansari, Peter B. Dervan. bioRxiv 2020.08.13.249730; doi: https://doi.org/10.1101/2020.08.13.249730.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:105017
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:18 Aug 2020 22:45
Last Modified:18 Aug 2020 22:45

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