MrRNA-directed DNA methylation enables selective mutant oncogene silencing therapy without exogenous proteins
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PROVIDER: PRJNA1303133 | ENA |
REPOSITORIES: ENA
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Project description:mrRNA-directed DNA methylation enables selective mutant oncogene silencing therapy without exogenous proteins [RRBS]
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Project description:The outcome of recent demethylation therapy is limited by the unspecific hypomethylation of oncogenes. The mechanism underlying differential DNA methylation distribution in the same topological domain remains unclear. Here, we established an efficient framework based on heterogeneity across pan-cancers to systemically characterize DNA methylation regulatory boxes (mrBoxes). Through plasmid-based functional motif interactome analysis assay, the role of mrBoxes on DNA methylation was validated. Moreover, the U1 small nuclear ribonucleoprotein A (SNPRA) was found to regulate the chromatin localization of DNMT1 to mrBox. In this process, long noncoding RNAs were identified to act as a bridge, connecting the targeted mrBox element and SNRPA/DNMT1 complex. Based on this regulatory model, we synthesized exogenous methylation-regulating RNA (mrRNA), which contains only the mrBox-recognizing and SNRPA/DNMT1 complex-binding motif. Furthermore, we developed a methylation-regulating therapy called “OncoMutation Silence”, which regulates the DNA methylation of mutated oncogenes through mrRNA. The efficacy and specificity of this therapy have been verified in tumors with KrasG12D mutation. Collectively, this study reveals mrBox-related regulatory model of DNA methylation, and provides mrRNA-based tumor therapy for silencing specific mutated oncogenes.
2025-08-12 | GSE304877 | GEO
Project description:The outcome of recent demethylation therapy is limited by the unspecific hypomethylation of oncogenes. The mechanism underlying differential DNA methylation distribution in the same topological domain remains unclear. Here, we established an efficient framework based on heterogeneity across pan-cancers to systemically characterize DNA methylation regulatory boxes (mrBoxes). Through plasmid-based functional motif interactome analysis assay, the role of mrBoxes on DNA methylation was validated. Moreover, the U1 small nuclear ribonucleoprotein A (SNPRA) was found to regulate the chromatin localization of DNMT1 to mrBox. In this process, long noncoding RNAs were identified to act as a bridge, connecting the targeted mrBox element and SNRPA/DNMT1 complex. Based on this regulatory model, we synthesized exogenous methylation-regulating RNA (mrRNA), which contains only the mrBox-recognizing and SNRPA/DNMT1 complex-binding motif. Furthermore, we developed a methylation-regulating therapy called “OncoMutation Silence”, which regulates the DNA methylation of mutated oncogenes through mrRNA. The efficacy and specificity of this therapy have been verified in tumors with KrasG12D mutation. Collectively, this study reveals mrBox-related regulatory model of DNA methylation, and provides mrRNA-based tumor therapy for silencing specific mutated oncogenes.
2025-08-26 | GSE306087 | GEO
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Project description:RNA-targeted degradation technologies offer significant promise for treating diseases by selectively disrupting gene expression. However, a robust method to specifically, efficiently, and programmability degrade targeted RNAs in mammalian cells is still in demand. Here, we present a versatile platform, dCas13d-directed chaperone-mediated autophagy (dCasCMA), which integrates the precise targeting capabilities of dCas13/CRISPR with the degradation efficiency of chaperone-mediated autophagy (CMA) to achieve efficient degradation of specific RNAs. By combining dCas13d with a CMA-targeting motif and customizable guide RNA (gRNA), the platform allows for accurate targeting of both exogenous and endogenous RNAs in cells. Moreover, the incorporation of multiplexed gRNA expression arrays enables the simultaneous degradation of multiple RNA targets during viral pathogenesis in live cells and in vivo. Our findings emphasize the platform’s modular design, which enables flexible combinations of dCCTM components with user-defined gRNA sequences. This versatility positions it as a promising tool for developing innovative therapies for various diseases.
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Project description:The development of floral organs plays a vital role in plant reproduction. In our research, the APETALA3 (AP3) promoter-transgenic lines showed abnormal developmental phenotypes in stamens and petals. The aim of this study is to understand the molecular mechanisms of the morphological defects in transgenic plants. By performing transgenic analysis, it was found that the AP3-promoted genes and the vector had no relation to the morphological defects. Then, we performed the expression analysis of the class A, B, and C genes. A dramatic reduction of transcript levels of class B genes (AP3 and PISTILLATA) was observed. Additionally, we also analyzed the methylation of the promoters of class B genes and found that the promoter of AP3 was hypermethylated. Furthermore, combining mutations in rdr2-2, drm1/2, and nrpd1b-11 with the AP3-silencing lines rescued the abnormal development of stamens and petals. The expression of AP3 was reactivated and the methylation level of AP3 promoter was also reduced in RdDM-defective AP3-silencing lines. Our results showed that the RdDM pathway contributed to the transcriptional silencing in the transgenic AP3-silencing lines. Moreover, the results revealed that fact that the exogenous fragment of a promoter could trigger the methylation of homologous endogenous sequences, which may be ubiquitous in transgenic plants.
| S-EPMC6770043 | biostudies-literature
Project description:The propagation of epigenetic marks has received a great deal of attention, yet the initiation of epigenetic silencing on a new transgene, virus, or transposable element remains incompletely characterized. The overlapping function of multiple silencing mechanisms has obscured this area of investigation. Here, we have revealed two broad mechanisms that are both able to initiate silencing independently: homology-based silencing and expression-dependent silencing. By transforming exogenous transposable elements into Arabidopsis, we circumvented homology-based silencing allowing us to isolate and investigate the molecular mechanism of expression-dependent silencing. We found that several small RNA-generating mechanisms all trigger de novo expression-dependent RNA-directed DNA methylation (RdDM) through RNA Polymerase V. In addition, the silencing of transposable elements fragments stalls at the RdDM phase, while full-length elements quickly progress through RdDM to maintenance methylation and heterochromatin formation. We found that there is a narrow window of time for the transition to a fully silenced state. Transformation into a mutant genotype followed by introgression into wild-type does not result in the same level of silencing as direct transformation into wild-type. This demonstrates that the genotype of transposable element insertion or transgene transformation is key for establishing the transgenerational extent of epigenetic silencing.
2017-08-25 | GSE86787 | GEO
Project description:Efficient C-H functionalization requires selectivity for specific C-H bonds. Progress has been made for directed aromatic substitution reactions to achieve ortho and meta selectivity, but a general strategy for para-selective C-H functionalization has remained elusive. Herein we introduce a previously unappreciated concept that enables nearly complete para selectivity. We propose that radicals with high electron affinity elicit arene-to-radical charge transfer in the transition state of radical addition, which is the factor primarily responsible for high positional selectivity. We demonstrate with a simple theoretical tool that the selectivity is predictable and show the utility of the concept through a direct synthesis of aryl piperazines. Our results contradict the notion, widely held by organic chemists, that radical aromatic substitution reactions are inherently unselective. The concept of radical substitution directed by charge transfer could serve as the basis for the development of new, highly selective C-H functionalization reactions.
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