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Published December 22, 2020 | Supplemental Material + Submitted + Published
Journal Article Open

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


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 technique confirms the ability of two eight ring hairpin-polyamides, with similar architectures but differing at a single ring position (Py to Im), to retain in vitro specificities and display distinct genome-wide binding profiles.

Additional Information

© 2020 Finn et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received: September 4, 2020; Accepted: December 1, 2020; Published: December 22, 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. Data Availability Statement: The data reported in this paper have been deposited in the NCBI Gene Expression Omnibus (accession no. GSE149367). Bio Informaticals provided support in the form of salaries for author [DB], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section. Bio Informaticals provides genomic data analysis service, with a particular focus on Cognate Site Identification (CSI) and COSMIC-seq. Competing interests: DB is a sole proprietor of Bio Informaticals (see www.bioinformaticals.com). This does not alter our adherence to PLOS ONE policies on sharing data and materials. Author Contributions: Conceptualization: Aseem Z. Ansari, Peter B. Dervan. Data curation: Paul B. Finn, Devesh Bhimsaria. Formal analysis: Paul B. Finn, Devesh Bhimsaria. Funding acquisition: Aseem Z. Ansari, Peter B. Dervan. Investigation: Paul B. Finn, Devesh Bhimsaria, Asfa Ali, Asuka Eguchi. Methodology: Paul B. Finn. Software: Devesh Bhimsaria. Supervision: Aseem Z. Ansari, Peter B. Dervan. Visualization: Paul B. Finn, Devesh Bhimsaria. Writing – original draft: Paul B. Finn, Devesh Bhimsaria, Aseem Z. Ansari, Peter B. Dervan. Writing – review & editing: Paul B. Finn, Devesh Bhimsaria, Asfa Ali, Asuka Eguchi, Aseem Z. Ansari, Peter B. Dervan.

Attached Files

Published - journal.pone.0243905.pdf

Submitted - 2020.08.13.249730v1.full.pdf

Supplemental Material - journal.pone.0243905.s001.tif

Supplemental Material - journal.pone.0243905.s002.tif

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Supplemental Material - journal.pone.0243905.s009.tiff

Supplemental Material - journal.pone.0243905.s010.pdf

Supplemental Material - journal.pone.0243905.s011.pdf


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Additional details

August 20, 2023
October 20, 2023