Inducible and reversible inhibition of miRNA-medaited gene repression in vivo
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA744226 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15054303_1.fastq.gz | Fastqsanger.gz | |||
| SRR15054303_2.fastq.gz | Fastqsanger.gz | |||
| SRR15054304_1.fastq.gz | Fastqsanger.gz | |||
| SRR15054304_2.fastq.gz | Fastqsanger.gz | |||
| SRR15054305_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 42 |
Similar Datasets
Project description:Although virtually all gene networks are predicted to be controlled by miRNAs, the contribution of this important layer of gene regulation to tissue homeostasis in adult animals remains unclear. Gain and loss-of-function experiments have provided key insights into the specific function of individual miRNAs, but effective genetic tools to study the functional consequences of global inhibition of miRNA activity in vivo are lacking. Here we report the generation and characterization of a genetically engineered mouse strain in which miRNA-mediated gene repression can be reversibly inhibited without affecting miRNA biogenesis or abundance. We demonstrate the usefulness of this strategy by investigating the consequences of acute inhibition of miRNA function in adult animals. We find that different tissues and organs respond differently to global loss of miRNA function. While miRNA-mediated gene repression is essential for the homeostasis of the heart and the skeletal muscle, it is largely dispensable in the majority of other organs. Even in tissues where it is not required for homeostasis, such as the intestine and hematopoietic system, miRNA activity can become essential during regeneration following acute injury. These data support a model where many metazoan tissues primarily rely on miRNA function to respond to potentially pathogenic events.
| S-EPMC8476124 | biostudies-literature
Project description:Although virtually all gene networks are predicted to be controlled by miRNAs, the contribution of this important layer of gene regulation to tissue homeostasis in adult animals remains unclear. Gain and loss of function experiments have provided key insights into the specific function of individual miRNAs, but effective genetic tools to study the functional consequences of global inhibition of miRNA activity in vivo are lacking. Here we report the generation and characterization of a genetically engineered mouse strain in which miRNA-mediated gene repression can be reversibly inhibited without affecting miRNA biogenesis or abundance. We demonstrate the usefulness of this strategy by investigating the consequences of acute inhibition of miRNA function in adult animals. We find that different tissues and organs respond differently to global loss of miRNA function. While miRNA-mediated gene repression is essential for the homeostasis of the heart and the skeletal muscle, it is largely dispensable in the majority of other organs. Even in tissues where it is not required for homeostasis, such as the intestine and hematopoietic system, miRNA activity can become essential during regeneration following acute injury. These data support a model where many metazoan tissues primarily rely on miRNA function to respond to potentially pathogenic events.
2021-07-07 | GSE179588 | GEO
Project description:An inducible and reversible embryonic stem cell biobank reveals functional genomic pathways and disease targets
| PRJNA328006 | ENA
Project description:Although several genes are implicated in the pathogenesis of schizophrenia, in animal models for such a severe mental illness only some aspects of the pathology can be represented (endophenotypes). Genetically modified mice are currently being used to obtain or characterize such endophenotypes. Since its cloning and characterization CB1 receptor has increasingly become of significant physiological, pharmacological and clinical interest. Recently, its involvement in schizophrenia has been reported. Among the different approaches employed, gene targeting permits to study the multiple roles of the endocannabinoid system using knockout ((-/-)) mice represent a powerful model but with some limitations due to compensation. To overcome such a limitation, we have generated an inducible and reversible tet-off dependent tissue-specific CB1(-/-) mice where the CB1R is re-expressed exclusively in the forebrain at a hypomorphic level due to a mutation (IRh-CB1(-/-)) only in absence of doxycycline (Dox). In such mice, under Dox(+) or vehicle, as well as in wild-type (WT) and CB1(-/-), two endophenotypes motor activity (increased in animal models of schizophrenia) and pre-pulse inhibition (PPI) of startle reflex (disrupted in schizophrenia) were analyzed. Both CB1(-/-) and IRh-CB1(-/-) showed increased motor activity when compared to WT animals. The PPI response, unaltered in WT and CB1(-/-) animals, was on the contrary highly and significantly disrupted only in Dox(+) IRh-CB1(-/-) mice. Such a response was easily reverted after either withdrawal from Dox or haloperidol treatment. This is the first Inducible and Reversible CB1(-/-) mice model to be described in the literature. It is noteworthy that the PPI disruption is not present either in classical full CB1(-/-) mice or following acute administration of rimonabant. Such a hypomorphic model may provide a new tool for additional in vivo and in vitro studies of the physiological and pathological roles of cannabinoid system in schizophrenia and in other psychiatric disorders.
| S-EPMC3338749 | biostudies-literature
Project description:A versatile in vivo platform for reversible control of transgene expression in adult tissues
| PRJNA1117865 | ENA
Project description:Temporal control of exogenous genes through artificial genetic circuits has advanced a range of biomedical interventions, including in vivo reprogramming. The doxycycline (Dox)-mediated Tet- ON system has been widely employed due to its highly reversible and tunable gene induction. Nonetheless, its effectiveness in vivo is limited by inherent resistance in some tissues. In the present study, mouse models were developed with the Tet-ON or complementary Tet-OFF system to thoroughly investigate the spatial and temporal control of transgene expression in adult tissues. The Tet-OFF system could induce gene expression in a broad spectrum of cell types, such as neuronal cells, cardiomyocytes, and skeletal muscle cells, in stark contrast with the Tet-ON system, which could only induce gene expression in particular tissues and cell types, mainly epithelial cells. Despite its broader reach, the Tet-OFF system exhibited slow inducibility and lacked tunability in the expression levels of transgenes. Capitalizing on the pharmacologic advantages of tetracycline (Tc), which has a shorter half-life in vivo and lower affinity for Tet repressor than Dox, we revisited its application. Remarkably, Tc enabled rapid, reversible, and graded control of transgene expression in the Tet-OFF system. Moreover, utilization of Tc mitigated the transcriptional perturbation associated with use of Dox. Our data suggest that the Tc-mediated Tet-OFF system not only enables more versatile control of transgene expression but may also offer a more biocompatible alternative, enhancing its suitability for applications such as tissue regeneration and organismal rejuvenation.
2025-02-05 | GSE268589 | GEO
Project description:Reversible p53 activation using a temperature variant of p53
2012-04-30 | E-MEXP-3224 | biostudies-arrayexpress
Project description:Activating Kras mutations are the hallmark genetic alterations in pancreatic ductal adenocarcinoma (PDAC) and key drivers of PDAC initiation and progression. Despite increased efforts to develop novel Kras inhibitors, the degree of Kras oncogene addiction in PDAC cells remains unclear. Here, we analyzed the requirement of endogenous Kras for the maintenance of murine PDAC cells using an inducible shRNA-based system that enables temporal control of endogenous Kras expression. Surprisingly, the majority of murine PDAC cells analyzed tolerated acute and sustained Kras knockdown by adapting to a reversible cell state, characterized by differences in cell morphology, proliferative kinetics, and tumor-initiating capacity. While significant mutational or transcriptional changes were not observed in the Kras-inhibited state, global phosphoproteomic profiling revealed alterations in cell signaling, including increased phosphorylation of focal adhesion pathway components. Accordingly, Kras-inhibited cells displayed prominent focal adhesion plaque structures, enhanced adherence properties, and increased dependency on adhesion for viability in vitro. Our analyses highlight the possibility of adaptive non-genetic and non-transcriptional mechanisms of resistance to Kras inhibition. Furthermore, we have identified candidate proteins whose signaling activities are altered in the Kras-inhibited state, providing a basis for the rational design of combination therapeutic strategies with novel Kras inhibitors.
2018-01-03 | GSE95478 | GEO
Project description:N1-methyladenosine (m1A) is an abundant post-transcriptional RNA modification, yet little is known about its prevalence, topology and dynamics in mRNA. Here, we show that m1A is abundant in human mRNA, with an m1A/A ratio of ~0.02%. We develop m1A-ID-Seq, based on m1A immunoprecipitation and the inherent property of m1A to stall reverse transcription, for the transcriptome-wide m1A analysis. m1A-ID-Seq identifies 901 m1A peaks (from 583 genes) in mRNA and ncRNA, and reveals a prominent feature of enrichment in the 5â-untranslated region of mRNA transcripts, distinct from that of N6-methyladenosine, the most abundant internal mammalian mRNA modification. m1A in mRNA is also reversible by ALKBH3, a known DNA/RNA demethylase. Lastly, m1A responds dynamically to stimuli and hundreds of stress-induced m1A sites are identified. Collectively, our approaches allow comprehensive analysis of m1A methylation and provide an important tool for functional studies of potential epigenetic regulation via the reversible and dynamic m1A methylation. Identification of m1A sites in human embryonic kidney cells. Comparisons of m1A profiles of wild type HEK293T with ALKBH3 knock out cell line reveals the ALKBH3 specific sites. Stress inducible m1A sites are also identified by comparing the profiles of untreated cells with stress treated cells.
2016-02-05 | E-GEOD-73941 | biostudies-arrayexpress
Project description:Inducible amiRNA expression in seedlings leads to repression of amiRNA target bZIP11 and thereby changed of bZIP11 target gene expression.
2021-09-09 | GSE139821 | GEO