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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. PLoS ONE, 15 (12). Art. No. e0243905. ISSN 1932-6203. https://resolver.caltech.edu/CaltechAUTHORS:20200818-152604358

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Abstract

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1371/journal.pone.0243905DOIArticle
https://doi.org/10.1101/2020.08.13.249730DOIDiscussion Paper
https://doi.org/10.1371/journal.pone.0243905.s001DOIS1 Fig.
https://doi.org/10.1371/journal.pone.0243905.s002DOIS2 Fig.
https://doi.org/10.1371/journal.pone.0243905.s003DOIS3 Fig.
https://doi.org/10.1371/journal.pone.0243905.s004DOIS4 Fig.
https://doi.org/10.1371/journal.pone.0243905.s005DOIS5 Fig.
https://doi.org/10.1371/journal.pone.0243905.s006DOIS6 Fig.
https://doi.org/10.1371/journal.pone.0243905.s007DOIS7 Fig.
https://doi.org/10.1371/journal.pone.0243905.s008DOIS8 Fig.
https://doi.org/10.1371/journal.pone.0243905.s009DOIS9 Fig.
https://doi.org/10.1371/journal.pone.0243905.s010DOIS1 File
https://doi.org/10.1371/journal.pone.0243905.s011DOIS2 File
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:© 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.
Group:Millard and Muriel Jacobs Genetics and Genomics Laboratory
Funders:
Funding AgencyGrant Number
Bio InformaticalsUNSPECIFIED
Issue or Number:12
Record Number:CaltechAUTHORS:20200818-152604358
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200818-152604358
Official Citation:Finn PB, Bhimsaria D, Ali A, Eguchi A, Ansari AZ, Dervan PB (2020) Single position substitution of hairpin pyrrole-imidazole polyamides imparts distinct DNA-binding profiles across the human genome. PLoS ONE 15(12): e0243905. https://doi.org/10.1371/journal. pone.0243905
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:22 Dec 2020 21:48

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