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Region-specific alteration of histone modification by LSD1 inhibitor conjugated with pyrrole-imidazole polyamide

ABSTRACT: Region-specific alteration of histone modification by LSD1 inhibitor conjugated with pyrrole-imidazole polyamide

PROVIDER: PRJNA423010 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6388640.fastq.gz	Fastqsanger.gz
	SRR6388650.fastq.gz	Fastqsanger.gz
	SRR6388641.fastq.gz	Fastqsanger.gz
	SRR6388651.fastq.gz	Fastqsanger.gz
	SRR6388642.fastq.gz	Fastqsanger.gz

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Antitumor activity of a pyrrole-imidazole polyamide

Project description:We report that a DNA minor groove binding hairpin pyrrole-imidazole (Py-Im) polyamide interferes with RNA polymerase II (RNAP2) activity in cell culture. Genome-wide mapping of RNAP2 binding shows reduction of occupancy preferentially at transcription start sites (TSS), while occupancy at enhancer sites are is unchanged. Genome-wide mapping of RNA polymerase II in LNCaP cells treated with DHT and DHT with Py-Im polyamide.

2013-01-31 | E-GEOD-43253 | biostudies-arrayexpress

Antitumor activity of a pyrrole-imidazole polyamide

2013-01-31 | GSE43253 | GEO

Alkylating pyrrole-imidazole polyamide KR12 binding in colorectal cancer genomes (SW480)

Project description:Pyrrole-imidazole polyamides are versatile DNA minor groove binders and attractive therapeutic options against oncological targets, especially upon functionalization with an alkylating agent such as endo-seco-CBI. These molecules also provide an alternative for oncogenes deemed “undruggable” at the protein level, where the absence of solvent-accessible pockets or structural crevices prevent the formation of protein-inhibitor ligands; nevertheless, the genome-wide effect of pyrrole-imidazole polyamide binding remain largely unclear to-date. Here we propose a next-generation sequencing-based workflow combined with whole genome expression arrays to address such issue using a candidate anti-cancer alkylating agent, KR12, against codon 12 mutant KRAS. Biotinylating KR12 enables the means to identify its genome-wide effects in living cells and possible biological implications via a coupled workflow of enrichment-based sequencing and expression microarrays. The subsequent computational pathway and expression analyses allow the identification of its genomic binding sites, as well as a route to explore a polyamide’s possible genome-wide effects. Among the 3,343 KR12 binding sites identified in the human LS180 colorectal cancer genome, the reduction of KR12-bound gene expressions was also observed. Additionally, the coupled microarray-sequencing analysis also revealed some insights about the effect of local chromatin structure on pyrrole-imidazole polyamide, which had not been fully understood to-date. A comparative analysis with KR12 in a different human colorectal cancer genome SW480 also showed agreeable agreements of KR12 binding affecting gene expressions. Combination of these analyses thus suggested the possibility of applying this approach to other pyrrole-imidazole polyamides to reveal further biological details about the effect of polyamide binding in a genome.

2016-11-01 | GSE86598 | GEO

Alkylating pyrrole-imidazole polyamide KR12 binding in colorectal cancer genomes (LS180)

2016-11-01 | GSE86597 | GEO

Pyrrole-imidazole polyamide targeted to the REL/ELK1 overlapping sequences in the EVI1 minimal promoter

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

Region-specific alteration of histone modification by LSD1 inhibitor conjugated with pyrrole-imidazole polyamide

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

Novel therapeutic strategy targeting STMN1 using chlorambucil-conjugated pyrrole-imidazole polyamide in small cell lung cancer

Project description:Novel therapeutic strategy targeting STMN1 using chlorambucil-conjugated pyrrole-imidazole polyamide in small cell lung cancer

| PRJNA1185706 | ENA

Pyrrole-imidazole polyamide targeted to the REL/ELK1 overlapping sequences in the EVI1 minimal promoter

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

Novel therapeutic strategy targeting STMN1 using chlorambucil-conjugated pyrrole-imidazole polyamide in small cell lung cancer

Project description:Introduction Small-cell lung cancer (SCLC) is an aggressive malignancy and its treatment has not progressed over the decades. Stathmin 1 (TMN1) is a cytoplasmic phosphorylated protein that is specific to cancerous tissues and is associated with malignancy. Pyrrole-imidazole polyamide (PIP) compounds decrease gene expression by binding to specific DNA sites and disturbing RNA transcription. In this study, we synthesized a novel Chlorambucil-conjugated PIP compound targeting both the STMN1 promoter and STMN1 DNA sequences (Chb-STMN1 PIP) to evaluate its therapeutic efficacy against SCLC. Methods We examined the expression of STMN1 in surgically resected lung cancer tissues and cell line database. Suppression of STMN1 by Chb-STMN1 PIP was analyzed using RT-PCR, WB, and CAGE-seq in vitro. The anti-tumor effects of Chb-STMN1 PIP were evaluated in vitro and in vivo. Results Chb-STMN1 PIP treatment resulted in significant STMN1 suppression and cell viability reduction compared to the Chb alone and Chb-control PIP groups. Administration of Chb-STMN1 PIP to an SCLC xenograft mouse model also showed a tumor reduction effect and significantly suppressed angiogenesis, proliferation potency, and cell viability of SCLC. CAGE analysis indicated that the transcription of STMN1 was suppressed in Chb-STMN1 PIP-treated cells compared to that in control cells. Conclusions A novel compound, Chb-STMN1 PIP, induced significant anti-tumor effects and suppressed STMN1 expression in SCLC cell lines. Furthermore, SCLC xenograft mouse models show tumor shrinkage and reduced malignant properties. Targeting STMN1 with our developed PIP compound appears to be a novel strategy and promising in SCLC.

2025-08-18 | GSE281782 | GEO

Alkylating pyrrole-imidazole polyamide KR12 binding in colorectal cancer genomes

Project description:Alkylating pyrrole-imidazole polyamide KR12 binding in colorectal cancer genomes

| PRJNA342329 | ENA