Targeted suppression of metastasis controlling transcription factor SOX2 in various cancers using a sequence-specific designer Pyrrole-Imidazole Polyamide
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE138617 | GEO | 2020/10/31
REPOSITORIES: GEO
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Project description:Pyrrole-imidazole polyamides (PIPs) have been shown to inhibit gene expression by interrupting the DNA-protein interface. Human Ectopic viral integration site 1 (EVI1) is an oncogenic transcription factor which plays a key role in many aggressive forms of cancer. We have developed a novel pyrroleM-bM-^@M-^Simidazole polyamide, PIP1 targeting the REL/ELK1 binding site in the EVI1 minimal promoter that can significantly repress the expression of EVI1 in MDA-MB-231 cells. Whole-transcriptome analysis revealed that a fraction of EVI1-driven genes were modulated by PIP1. Global expression changes in MDA-MB-231 cells were evaluated after treating the cells with PIP1 and DMSO for 48 hours. The vehicle DMSO is used as a negative control. Each condition is performed in technical replicates.
2014-07-28 | E-GEOD-59502 | biostudies-arrayexpress
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
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 | GSE124455 | GEO
Project description:Pyrrole-imidazole polyamides (PIPs) have been shown to inhibit gene expression by interrupting the DNA-protein interface. Human Ectopic viral integration site 1 (EVI1) is an oncogenic transcription factor which plays a key role in many aggressive forms of cancer. We have developed a novel pyrrole–imidazole polyamide, PIP1 targeting the REL/ELK1 binding site in the EVI1 minimal promoter that can significantly repress the expression of EVI1 in MDA-MB-231 cells. Whole-transcriptome analysis revealed that a fraction of EVI1-driven genes were modulated by PIP1.
2014-07-28 | GSE59502 | 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 | 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 | GSE124461 | GEO
Project description:We conjugated NCD38 with two different Py-Im polyamides and analyzed the regions epigenetically altered by parental NCD38 and the two conjugates.
2018-07-31 | GSE108265 | GEO