Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA237792 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Disrupted iron homeostasis causes dopaminergic neurodegeneration in mice
| PRJNA277823 | ENA
Project description:Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) have been discovered in several cancer types and cause the neurometabolic syndrome D2-Hydroxyglutaric aciduria (D2HGA). The mutant enzymes exhibit neomorphic activity resulting in production of D2- hydroxyglutaric acid (D-2HG). To study the pathophysiological consequences of the accumulation of D2-HG, we generated transgenic mice with conditionally activated IDH2R140Q and IDH2R172K alleles. Global induction of mutant IDH2 expression in adults resulted in dilated cardiomyopathy, white matter abnormalities throughout the central nervous system (CNS), and muscular dystrophy. Embryonic activation of mutant IDH2 resulted in more pronounced phenotypes, including runting, hydrocephalus, and shortened life span—recapitulating the abnormalities observed in D2HGA patients. The diseased hearts exhibited mitochondrial damage and glycogen accumulation with a concordant upregulation of genes involved in glycogen biosynthesis. Notably, mild cardiac hypertrophy was also observed in nude mice implanted with IDH2R140Q expressing xenografts, suggesting that 2HG may potentially act in a paracrine fashion. Finally, we show that silencing of IDH2R140Q in mice with an inducible transgene restores heart function by lowering 2HG levels. Together, these findings indicate that inhibitors of mutant IDH2 may be beneficial in the treatment of D2HGA and suggest that 2HG produced by IDH mutant tumors has the potential to provoke a paraneoplastic condition. We have performed microarray expression profiling of hearts from IDH2 mutant and control mice.
2014-03-01 | E-GEOD-54838 | biostudies-arrayexpress
Project description:The acetylation levels of histones and other proteins change during aging and have been linked to neurodegeneration. Here we show that deletion of the histone acetyltransferase (HAT) co-factor Trrap specifically impairs the function of the transcription factor Sp1, reduces its stability and causes a decrease in histone acetylation at Sp1 target genes. Modulation of Sp1 function by Trrap acts as a hub regulating multiple processes involved in neuron and neural stem cells function and maintenance including microtubule dynamics and the Wnt signaling pathway. Consistently, Trrap conditional mutants exhibit all hallmarks of neurodegeneration including dendrite retraction and axonal swellings, neuron death, astrogliosis, microglia activation, demyelination and decreased adult neurogenesis. Our results uncovered a novel functional network, essential to prevent neurodegeneration, and involving the specific regulation of Sp1 transcription factor and its downstream targets by Trrap-HAT.
2021-02-17 | GSE131283 | GEO
Project description:Mutations in IDH1 and IDH2 are frequently observed in various cancers, including acute myeloid leukemia (AML). Mutant IDHs convert α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG), which dysregulates a set ofα-KG-dependent dioxygenases. To determine whether mutant IDHs are valid targets for cancer therapy, we established a mouse AML model harboring an IDH2 mutation by transplanting mice with nucleophosmin1 (NPM1)+/- mouse hematopoietic stem/progenitor cells that had been co-transduced with four mutant genes (NPMc, IDH2/R140Q, DNMT3A/R882H and FLT3/ITD) that frequently occur simultaneously in human AML patients. IDH2/R140Q is necessary for the engraftment or survival of NPMc+ cells in vivo. Gene-expression analysis indicated that NPMc increased the expression of Hoxa9, and that IDH2/R140Q increased the level of Meis1 and activated the hypoxia pathway in AML cells. Conditional deletion of IDH2/R140Q blocked 2-HG production and maintenance of leukemia stem cells, resulting in survival of the AML mice. IDH2/R140Q reversibly decreased the levels of 5hmC modification and gene expression at some differentiation inducing genes (Ebf1, Pax5 and Spib). These results indicate that the IDH2 mutation is critical for the development and maintenance of AML stem cells, and that mutant IDHs are promising targets for anticancer therapy.
2015-03-25 | GSE63635 | GEO
Project description:Mutations in IDH1 and IDH2 are frequently observed in various cancers, including acute myeloid leukemia (AML). Mutant IDHs convert α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG), which dysregulates a set ofα-KG-dependent dioxygenases. To determine whether mutant IDHs are valid targets for cancer therapy, we established a mouse AML model harboring an IDH2 mutation by transplanting mice with nucleophosmin1 (NPM1)+/- mouse hematopoietic stem/progenitor cells that had been co-transduced with four mutant genes (NPMc, IDH2/R140Q, DNMT3A/R882H and FLT3/ITD) that frequently occur simultaneously in human AML patients. IDH2/R140Q is necessary for the engraftment or survival of NPMc+ cells in vivo. Gene-expression analysis indicated that NPMc increased the expression of Hoxa9, and that IDH2/R140Q increased the level of Meis1 and activated the hypoxia pathway in AML cells. Conditional deletion of IDH2/R140Q blocked 2-HG production and maintenance of leukemia stem cells, resulting in survival of the AML mice. IDH2/R140Q reversibly decreased the levels of 5hmC modification and gene expression at some differentiation inducing genes (Ebf1, Pax5 and Spib). These results indicate that the IDH2 mutation is critical for the development and maintenance of AML stem cells, and that mutant IDHs are promising targets for anticancer therapy.
2015-03-25 | GSE63618 | GEO
Project description:More than 50% of patients with chondrosarcomas exhibit gain-of-function mutations in either isocitrate dehydrogenase 1 (IDH1) or IDH2. In this study, we performed genome-wide CpG methylation sequencing of chondrosarcoma biopsies and found that IDH mutations were associated with DNA hypermethylation at CpG islands but not other genomic regions. Regions of CpG island hypermethylation were enriched for genes implicated in stem cell maintenance/differentiation and lineage specification. In murine 10T1/2 mesenchymal 20 progenitor cells, expression of mutant IDH2 led to DNA hypermethylation and an impairment in differentiation that could be reversed by treatment with DNA-hypomethylating agents. Introduction of mutant IDH2 also induced loss of contact inhibition and generated undifferentiated sarcomas in vivo. The oncogenic potential of mutant IDH2 correlated with the ability to produce 2-hydroxyglutarate. Together, these data demonstrate that neomorphic IDH2 mutations can be oncogenic in mesenchymal cells.. RRBS sequencing of (1) IDH wild type and mutant human chondrosarcomas, (2) isogenic cell lines expressing wild-type or mutant IDH.
2013-10-21 | E-GEOD-50539 | biostudies-arrayexpress
Project description:Introgressed variants from other species can be an important source of genetic variation because they may arise rapidly, can include multiple mutations on a single haplotype, and have often been pretested by selection in the species of origin. Although introgressed alleles are generally deleterious, several studies have reported introgression as the source of adaptive alleles-including the rodenticide-resistant variant of Vkorc1 that introgressed from Mus spretus into European populations of Mus musculus domesticus. Here, we conducted bidirectional genome scans to characterize introgressed regions into one wild population of M. spretus from Spain and three wild populations of M. m. domesticus from France, Germany, and Iran. Despite the fact that these species show considerable intrinsic postzygotic reproductive isolation, introgression was observed in all individuals, including in the M. musculus reference genome (GRCm38). Mus spretus individuals had a greater proportion of introgression compared with M. m. domesticus, and within M. m. domesticus, the proportion of introgression decreased with geographic distance from the area of sympatry. Introgression was observed on all autosomes for both species, but not on the X-chromosome in M. m. domesticus, consistent with known X-linked hybrid sterility and inviability genes that have been mapped to the M. spretus X-chromosome. Tract lengths were generally short with a few outliers of up to 2.7 Mb. Interestingly, the longest introgressed tracts were in olfactory receptor regions, and introgressed tracts were significantly enriched for olfactory receptor genes in both species, suggesting that introgression may be a source of functional novelty even between species with high barriers to gene flow.
| S-EPMC8784167 | biostudies-literature
Project description:Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) have been discovered in several cancer types and cause the neurometabolic syndrome D2-Hydroxyglutaric aciduria (D2HGA). The mutant enzymes exhibit neomorphic activity resulting in production of D2- hydroxyglutaric acid (D-2HG). To study the pathophysiological consequences of the accumulation of D2-HG, we generated transgenic mice with conditionally activated IDH2R140Q and IDH2R172K alleles. Global induction of mutant IDH2 expression in adults resulted in dilated cardiomyopathy, white matter abnormalities throughout the central nervous system (CNS), and muscular dystrophy. Embryonic activation of mutant IDH2 resulted in more pronounced phenotypes, including runting, hydrocephalus, and shortened life span—recapitulating the abnormalities observed in D2HGA patients. The diseased hearts exhibited mitochondrial damage and glycogen accumulation with a concordant upregulation of genes involved in glycogen biosynthesis. Notably, mild cardiac hypertrophy was also observed in nude mice implanted with IDH2R140Q expressing xenografts, suggesting that 2HG may potentially act in a paracrine fashion. Finally, we show that silencing of IDH2R140Q in mice with an inducible transgene restores heart function by lowering 2HG levels. Together, these findings indicate that inhibitors of mutant IDH2 may be beneficial in the treatment of D2HGA and suggest that 2HG produced by IDH mutant tumors has the potential to provoke a paraneoplastic condition.
2014-03-01 | GSE54838 | GEO
Project description:Loss of the Melanocortin 4 Receptor in mice causes dilated cardiomyopathy.
| PRJNA385096 | ENA
Project description:We collected whole genome testis expression data from hybrid zone mice. We integrated GWAS mapping of testis expression traits and low testis weight to gain insight into the genetic basis of hybrid male sterility.
2014-12-04 | GSE61417 | GEO