MiRNA hijacking for self-modulating oligonucleotide therapy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA855253 | ENA |
REPOSITORIES: ENA
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Project description:Due to a pivotal role in the post-transcriptional regulation of gene expressions implicated in numerous human diseases, miRNAs have been positioned to serve as promising disease biomarkers and novel therapeutic targets. However, gene silencing by miRNAs is limited to transcripts that contain complementary sequences. Herein we describe a miRNA-hijacker capable of downregulating newly assigned target mRNAs by hijacking intended miRNA. We developed a linear miRNA-hijacker with two miRNA binding sites to achieve higher repression and a hairpin-type (HT) miRNA-hijacker gifted with the hidden target mRNA binding site to minimize off-target effects. We also verified that the repression process by the miRNA-hijacker essentially involves the active mediating miRNA and functional AGO-RISC complex. By engineering the miRNA-hijackers to downregulate the anti-apoptotic BCL-xL gene, we successfully induced apoptosis only in the breast cancer cells overexpressing specific miRNAs and further validated its therapeutic efficacy in vivo, significantly reducing the tumor volume of the xenograft mouse upon its tail-vein injection. Our miRNA-hijacker technology can establish a new platform for self-modulating oligonucleotide therapy by hijacking disease-associated miRNAs and changing their destinations
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Project description:Microarrays offer a powerful tool for diverse applications plant biology and crop improvement. Recently, a global assembly of cotton ESTs was constructed based on three Gossypium. Using that assembly as a template, we now describe the design and creation and of a publicly available oligonucleotide array for cotton, useful for all four of the cultivated species. Synthetic oligonucleotide probes were generated from exemplar sequences of a global assembly of more than 150,000 cotton ESTs derived from 30 different cDNA libraries representing many different tissue types and tissue treatments. A total of 13,158 oligonucleotide probes are included on the arrays, optimized to target the diversity of the transcriptome but also including previously studied cotton genes, duplicated gene pairs derived from a paleoduplication event, transcription factors, and homology to protein coding genes in Arabidopsis. About 10% of the oligonucleotides target unidentified protein coding sequences, thereby providing an element of gene discovery. Because many oligonucleotides were based on ESTs from fiber-specific cDNA libraries, the array has direct application for analysis of the fiber transcriptome. To illustrate the utility of the array, we hybridized labeled bud and leaf cDNAs from G. hirsutum and demonstrate technical consistency of results. The cotton microarray provides a reproducible platform for transcription profiling in cotton, and is made publicly available through http://cottonevolution.info. Keywords: self vs. self; platform testing
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Project description:Enhancer hijacking, caused by structural alterations, is a common cancer driver event that causes aberrant expression of oncogenes. Unfortunately, enhancer hijacking is difficult to detect due to the complexity of the cancer genome. Here we propose a simple yet robust strategy HAPI (Highly Active Promoter Interactions) to identify and characterize such events by following two rules: 1) oncogenes subject to enhancer hijacking should be potentially highly regulated by enhancers, 2) the hijacked enhancers should contribute an appreciable proportion of an oncogene’s overall enhancer activity. Applying this strategy to HiChIP data we and others generated in 34 cancer cell lines, we identified known enhancer hijacking events and uncovered novel enhancers hijacked by known or potentially novel oncogenes such as CCND1, ETV1, ID4, and NKX2-5, which we validated using CRISPRi assays and RNA-seq analysis. Furthermore, we found that complex enhancer hijacking events connecting genes and enhancers from multiple chromosomal segments are often caused by the formation of extrachromosomal circular DNA (ecDNA). Focusing on ecDNAs harboring the MYC oncogene, one of the most common gene targets of ecDNA, we found that these ecDNAs often stitch additional genes such as CDX2, ERBB2, and NFIB from other chromosomes to the MYC locus. These genes heavily hijack MYC enhancers for their activation, a novel insight into ecDNA biology, suggesting alternative therapeutic targets for MYC ecDNAs. Our study provides an efficient strategy to detect enhancer hijacking events, and more importantly reveals novel mechanisms underlying oncogene activation caused by simple or complex structural alterations.
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Project description:Enhancer hijacking, caused by structural alterations, is a common cancer driver event that causes aberrant expression of oncogenes. Unfortunately, enhancer hijacking is difficult to detect due to the complexity of the cancer genome. Here we propose a simple yet robust strategy HAPI (Highly Active Promoter Interactions) to identify and characterize such events by following two rules: 1) oncogenes subject to enhancer hijacking should be potentially highly regulated by enhancers, 2) the hijacked enhancers should contribute an appreciable proportion of an oncogene’s overall enhancer activity. Applying this strategy to HiChIP data we and others generated in 34 cancer cell lines, we identified known enhancer hijacking events and uncovered novel enhancers hijacked by known or potentially novel oncogenes such as CCND1, ETV1, ID4, and NKX2-5, which we validated using CRISPRi assays and RNA-seq analysis. Furthermore, we found that complex enhancer hijacking events connecting genes and enhancers from multiple chromosomal segments are often caused by the formation of extrachromosomal circular DNA (ecDNA). Focusing on ecDNAs harboring the MYC oncogene, one of the most common gene targets of ecDNA, we found that these ecDNAs often stitch additional genes such as CDX2, ERBB2, and NFIB from other chromosomes to the MYC locus. These genes heavily hijack MYC enhancers for their activation, a novel insight into ecDNA biology, suggesting alternative therapeutic targets for MYC ecDNAs. Our study provides an efficient strategy to detect enhancer hijacking events, and more importantly reveals novel mechanisms underlying oncogene activation caused by simple or complex structural alterations.
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Project description:Enhancer hijacking, caused by structural alterations, is a common cancer driver event that causes aberrant expression of oncogenes. Unfortunately, enhancer hijacking is difficult to detect due to the complexity of the cancer genome. Here we propose a simple yet robust strategy HAPI (Highly Active Promoter Interactions) to identify and characterize such events by following two rules: 1) oncogenes subject to enhancer hijacking should be potentially highly regulated by enhancers, 2) the hijacked enhancers should contribute an appreciable proportion of an oncogene’s overall enhancer activity. Applying this strategy to HiChIP data we and others generated in 34 cancer cell lines, we identified known enhancer hijacking events and uncovered novel enhancers hijacked by known or potentially novel oncogenes such as CCND1, ETV1, ID4, and NKX2-5, which we validated using CRISPRi assays and RNA-seq analysis. Furthermore, we found that complex enhancer hijacking events connecting genes and enhancers from multiple chromosomal segments are often caused by the formation of extrachromosomal circular DNA (ecDNA). Focusing on ecDNAs harboring the MYC oncogene, one of the most common gene targets of ecDNA, we found that these ecDNAs often stitch additional genes such as CDX2, ERBB2, and NFIB from other chromosomes to the MYC locus. These genes heavily hijack MYC enhancers for their activation, a novel insight into ecDNA biology, suggesting alternative therapeutic targets for MYC ecDNAs. Our study provides an efficient strategy to detect enhancer hijacking events, and more importantly reveals novel mechanisms underlying oncogene activation caused by simple or complex structural alterations.
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Project description:Enhancing chimeric antigen receptor T cell therapy by modulating the p53 signaling network with Δ133p53α
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