COSMIC-seq of bioactive N-methylpyrrole/N-methylimidazole polyamides
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE70267 | GEO | 2016/11/08
SECONDARY ACCESSION(S): PRJNA321205
REPOSITORIES: GEO
Similar Datasets
Project description: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 de-signed 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 binding energetics. Determining the impact of genomic architecture and the local chromatin landscape on polyamide-DNA sequence specificity remains an unresolved question that impedes their utility in vivo. In this report we directly identified polyamide–DNA interaction sites across the entire genome, by covalent 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 and the potential for utility as synthetic transcription factors (Syn-TFs) capable of functioning in concert with the cellular regulatory circuitry.
2020-12-02 | GSE149367 | GEO
Project description:COSMIC-seq of bioactive hairpin N-methylpyrrole/N-methylimidazole polyamides
| PRJNA628512 | ENA
Project description:COSMIC-seq of bioactive N-methylpyrrole/N-methylimidazole polyamides
| PRJNA321205 | ENA
Project description:Side and off-target effects remain a difficult issue in the search of pharmaceutical leads, especially with DNA-binding molecules or genome editing methods where the issue becomes particularly thorny. A particular case is the investigations into the off-target effects of N-methylpyrrole-N-methylimidazole polyamides, a naturally inspired class of DNA binders that discriminately access the minor groove with strong affinity and sequence specificity but the relatively short motif of < 20 bases often imply possible non-unique genomic binding. Multiple binding sites may translate to binding at non-intended loci, potentially leading to off-target effects, issues that very few approaches are able to address to-date. We here report an analytical method of inferring off-target binding from expression profiling based on the relative impact to various biochemical pathways, as well as an accompanying side effect prediction engine to allow candidate polyamides to be systematically screened. This method marks the first attempt in PI polyamide research to identify elements in various biochemical pathways sensitive to the treatment of a candidate polyamide to infer possible off-target effects. Expression changes were then considered for their possible effect on outward phenotypic changes, manifested as side effects, should the same PI polyamide candidate be administered clinically. We also performed a series of animal experiments to validate some of these effects, and found some corroboration in certain side effect manifestations, such as changes in the level of aspartate transaminase in ICR and nude mice after injection of some of the candidate polyamides in this study.
2019-04-09 | GSE124456 | GEO
Project description:Side and off-target effects remain a difficult issue in the search of pharmaceutical leads, especially with DNA-binding molecules or genome editing methods where the issue becomes particularly thorny. A particular case is the investigations into the off-target effects of N-methylpyrrole-N-methylimidazole polyamides, a naturally inspired class of DNA binders that discriminately access the minor groove with strong affinity and sequence specificity but the relatively short motif of < 20 bases often imply possible non-unique genomic binding. Multiple binding sites may translate to binding at non-intended loci, potentially leading to off-target effects, issues that very few approaches are able to address to-date. We here report an analytical method of inferring off-target binding from expression profiling based on the relative impact to various biochemical pathways, as well as an accompanying side effect prediction engine to allow candidate polyamides to be systematically screened. This method marks the first attempt in PI polyamide research to identify elements in various biochemical pathways sensitive to the treatment of a candidate polyamide to infer possible off-target effects. Expression changes were then considered for their possible effect on outward phenotypic changes, manifested as side effects, should the same PI polyamide candidate be administered clinically. We also performed a series of animal experiments to validate some of these effects, and found some corroboration in certain side effect manifestations, such as changes in the level of aspartate transaminase in ICR and nude mice after injection of some of the candidate polyamides in this study.
2019-04-09 | GSE124455 | GEO
Project description:Side and off-target effects remain a difficult issue in the search of pharmaceutical leads, especially with DNA-binding molecules or genome editing methods where the issue becomes particularly thorny. A particular case is the investigations into the off-target effects of N-methylpyrrole-N-methylimidazole polyamides, a naturally inspired class of DNA binders that discriminately access the minor groove with strong affinity and sequence specificity but the relatively short motif of < 20 bases often imply possible non-unique genomic binding. Multiple binding sites may translate to binding at non-intended loci, potentially leading to off-target effects, issues that very few approaches are able to address to-date. We here report an analytical method of inferring off-target binding from expression profiling based on the relative impact to various biochemical pathways, as well as an accompanying side effect prediction engine to allow candidate polyamides to be systematically screened. This method marks the first attempt in PI polyamide research to identify elements in various biochemical pathways sensitive to the treatment of a candidate polyamide to infer possible off-target effects. Expression changes were then considered for their possible effect on outward phenotypic changes, manifested as side effects, should the same PI polyamide candidate be administered clinically. We also performed a series of animal experiments to validate some of these effects, and found some corroboration in certain side effect manifestations, such as changes in the level of aspartate transaminase in ICR and nude mice after injection of some of the candidate polyamides in this study.
2019-04-09 | GSE124461 | GEO
Project description:Side and off-target effects remain a difficult issue in the search of pharmaceutical leads, especially with DNA-binding molecules or genome editing methods where the issue becomes particularly thorny. A particular case is the investigations into the off-target effects of N-methylpyrrole-N-methylimidazole polyamides, a naturally inspired class of DNA binders that discriminately access the minor groove with strong affinity and sequence specificity but the relatively short motif of < 20 bases often imply possible non-unique genomic binding. Multiple binding sites may translate to binding at non-intended loci, potentially leading to off-target effects, issues that very few approaches are able to address to-date. We here report an analytical method of inferring off-target binding from expression profiling based on the relative impact to various biochemical pathways, as well as an accompanying side effect prediction engine to allow candidate polyamides to be systematically screened. This method marks the first attempt in PI polyamide research to identify elements in various biochemical pathways sensitive to the treatment of a candidate polyamide to infer possible off-target effects. Expression changes were then considered for their possible effect on outward phenotypic changes, manifested as side effects, should the same PI polyamide candidate be administered clinically. We also performed a series of animal experiments to validate some of these effects, and found some corroboration in certain side effect manifestations, such as changes in the level of aspartate transaminase in ICR and nude mice after injection of some of the candidate polyamides in this study.
2019-04-09 | GSE124460 | GEO
Project description:Side and off-target effects remain a difficult issue in the search of pharmaceutical leads, especially with DNA-binding molecules or genome editing methods where the issue becomes particularly thorny. A particular case is the investigations into the off-target effects of N-methylpyrrole-N-methylimidazole polyamides, a naturally inspired class of DNA binders that discriminately access the minor groove with strong affinity and sequence specificity but the relatively short motif of < 20 bases often imply possible non-unique genomic binding. Multiple binding sites may translate to binding at non-intended loci, potentially leading to off-target effects, issues that very few approaches are able to address to-date. We here report an analytical method of inferring off-target binding from expression profiling based on the relative impact to various biochemical pathways, as well as an accompanying side effect prediction engine to allow candidate polyamides to be systematically screened. This method marks the first attempt in PI polyamide research to identify elements in various biochemical pathways sensitive to the treatment of a candidate polyamide to infer possible off-target effects. Expression changes were then considered for their possible effect on outward phenotypic changes, manifested as side effects, should the same PI polyamide candidate be administered clinically. We also performed a series of animal experiments to validate some of these effects, and found some corroboration in certain side effect manifestations, such as changes in the level of aspartate transaminase in ICR and nude mice after injection of some of the candidate polyamides in this study.
2019-04-09 | GSE124459 | GEO
Project description:Side and off-target effects remain a difficult issue in the search of pharmaceutical leads, especially with DNA-binding molecules or genome editing methods where the issue becomes particularly thorny. A particular case is the investigations into the off-target effects of N-methylpyrrole-N-methylimidazole polyamides, a naturally inspired class of DNA binders that discriminately access the minor groove with strong affinity and sequence specificity but the relatively short motif of < 20 bases often imply possible non-unique genomic binding. Multiple binding sites may translate to binding at non-intended loci, potentially leading to off-target effects, issues that very few approaches are able to address to-date. We here report an analytical method of inferring off-target binding from expression profiling based on the relative impact to various biochemical pathways, as well as an accompanying side effect prediction engine to allow candidate polyamides to be systematically screened. This method marks the first attempt in PI polyamide research to identify elements in various biochemical pathways sensitive to the treatment of a candidate polyamide to infer possible off-target effects. Expression changes were then considered for their possible effect on outward phenotypic changes, manifested as side effects, should the same PI polyamide candidate be administered clinically. We also performed a series of animal experiments to validate some of these effects, and found some corroboration in certain side effect manifestations, such as changes in the level of aspartate transaminase in ICR and nude mice after injection of some of the candidate polyamides in this study.
2019-04-09 | GSE124458 | GEO
Project description:Side and off-target effects remain a difficult issue in the search of pharmaceutical leads, especially with DNA-binding molecules or genome editing methods where the issue becomes particularly thorny. A particular case is the investigations into the off-target effects of N-methylpyrrole-N-methylimidazole polyamides, a naturally inspired class of DNA binders that discriminately access the minor groove with strong affinity and sequence specificity but the relatively short motif of < 20 bases often imply possible non-unique genomic binding. Multiple binding sites may translate to binding at non-intended loci, potentially leading to off-target effects, issues that very few approaches are able to address to-date. We here report an analytical method of inferring off-target binding from expression profiling based on the relative impact to various biochemical pathways, as well as an accompanying side effect prediction engine to allow candidate polyamides to be systematically screened. This method marks the first attempt in PI polyamide research to identify elements in various biochemical pathways sensitive to the treatment of a candidate polyamide to infer possible off-target effects. Expression changes were then considered for their possible effect on outward phenotypic changes, manifested as side effects, should the same PI polyamide candidate be administered clinically. We also performed a series of animal experiments to validate some of these effects, and found some corroboration in certain side effect manifestations, such as changes in the level of aspartate transaminase in ICR and nude mice after injection of some of the candidate polyamides in this study.
2019-04-09 | GSE124457 | GEO