Single position substitution of hairpin pyrrole-imidazole polyamides imparts distinct DNA-binding profiles across the human genome
| Autor: | Asuka Eguchi, Asfa Ali, Paul B. Finn, Devesh Bhimsaria, Peter B. Dervan, Aseem Z. Ansari |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Gene Expression
Sequence (biology) 01 natural sciences Genome Mass Spectrometry Analytical Chemistry Database and Informatics Methods Binding Analysis chemistry.chemical_compound Spectrum Analysis Techniques Matrix-Assisted Laser Desorption Ionization Time-of-Flight Mass Spectrometry 0303 health sciences Multidisciplinary Chromosome Biology Imidazoles Genomics Chromatin DNA-Binding Proteins Chemistry Physical Sciences Medicine Epigenetics Sequence Analysis Research Article Bioinformatics Science Computational biology Research and Analysis Methods 010402 general chemistry Human Genomics DNA sequencing 03 medical and health sciences In vivo Sequence Motif Analysis Sequence-specific DNA binding Genetics Humans Pyrroles Chemical Characterization 030304 developmental biology Genome Human Biology and Life Sciences Cell Biology In vitro 0104 chemical sciences Nylons chemistry Genetic Loci Biophysics Nucleic Acid Conformation Human genome DNA |
| Zdroj: | PLoS ONE, Vol 15, Iss 12, p e0243905 (2020) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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