RNA-Seq of Aged Polg Mutator Mouse Brains
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE55188 | GEO | 2015/02/18
SECONDARY ACCESSION(S): PRJNA238836
REPOSITORIES: GEO
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Project description:We have performed both proteomic and transcriptomic analyses of the brains of one-year old Polg mutator mice. As part of this analysis, we generated RNA-Seq data from RNA isolated from one cerebral hemisphere of these mice. mRNA levels and protein abundance levels were compared in this study. 11 samples of RNA isolated from mouse cerebral hemisphere. 7 Polg D257A/D257A, 1 Polg D257A/WT, and 3 Polg WT/WT. The samples were collected from one-year old male mice.
2015-02-18 | E-GEOD-55188 | biostudies-arrayexpress
Project description:The goal of this study was to characterize gene expression profiles of wild-type (WT) and POLG D257A/D257A mutator (POLG mutator) macrophages at rest and 6 hours after lipopolysaccharide (LPS) challenge.
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Project description:Somatic mitochondrial DNA (mtDNA) mutations contribute to the pathogenesis of age-related disorders, including myelodysplastic syndromes (MDS). The accumulation of mitochondria harboring mtDNA mutations in patients with these disorders suggests a failure of normal mitochondrial quality-control systems. The mtDNA-mutator mice acquire somatic mtDNA mutations via a targeted defect in the proofreading function of the mtDNA polymerase, PolgA, and develop macrocyticanemia similar to that of patients with MDS. We observed an unexpected defect in clearance of dysfunctional mitochondria at specific stages during erythroid maturation in hematopoietic cells from aged mtDNA-mutator mice. Mechanistically, aberrant activation of mechanistic target of rapamycin signaling and phosphorylation of uncoordinated 51-like kinase (ULK) 1 in mtDNA-mutator mice resulted in proteasome mediated degradation of ULK1 and inhibition of autophagy in erythroid cells. To directly evaluate the consequence of inhibiting autophagy on mitochondrial function in erythroid cells harboring mtDNA mutations in vivo, we deleted Atg7 from erythroid progenitors of wildtype and mtDNA-mutator mice. Genetic disruption of autophagy did not cause anemia in wild-type mice but accelerated the decline in mitochondrial respiration and development of macrocytic anemia in mtDNA-mutator mice. These findings highlight a pathological feedback loop that explains how dysfunctional mitochondria can escape autophagy-mediated degradation and propagate in cells predisposed to somatic mtDNA mutations, leading to disease. We used microarrays to identify expression profiles and pathways that are differentially activated or suppressed in Ter119+ bone marrow cells isolated from phlebotomized wildtype or Polg mutant mice
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Project description:Transcriptomic analysis of WT and POLG mutator macrophages
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Project description:RNAsequencing data from POLG D257A mutant mouse iPS (induced pluripotent stem) cells. These mice accumulate random point mutations in their mitochondrial genome and manifest progeric features. The reprogramming and phenotype of the cells is described in Hämäläinen et al. 2015, Cell reports, mtDNA Mutagenesis Disrupts Pluripotent Stem Cell Function by Altering Redox Signaling. The goal of the study was to analyze altered gene expression profiles between mutant and wt iPS cells to identify altered biological pathways responsible for the stemness and proliferation defects seem in mtDNA mutator stem cells.
2019-09-24 | GSE133259 | GEO
Project description:Somatic mitochondrial DNA (mtDNA) mutations contribute to the pathogenesis of age-related disorders, including myelodysplastic syndromes (MDS). The accumulation of mitochondria harboring mtDNA mutations in patients with these disorders suggests a failure of normal mitochondrial quality-control systems. The mtDNA-mutator mice acquire somatic mtDNA mutations via a targeted defect in the proofreading function of the mtDNA polymerase, PolgA, and develop macrocytic anemia similar to that of patients with MDS. We observed an unexpected defect in clearance of dysfunctional mitochondria at specific stages during erythroid maturation in hematopoietic cells from aged mtDNA-mutator mice. Mechanistically, aberrant activation of mechanistic target of rapamycin signaling and phosphorylation of uncoordinated 51-like kinase (ULK) 1 in mtDNA-mutator mice resulted in proteasome mediated degradation of ULK1 and inhibition of autophagy in erythroid cells. To directly evaluate the consequence of inhibiting autophagy on mitochondrial function in erythroid cells harboring mtDNA mutations in vivo, we deleted Atg7 from erythroid progenitors of wildtype and mtDNA-mutator mice. Genetic disruption of autophagy did not cause anemia in wild-type mice but accelerated the decline in mitochondrial respiration and development of macrocytic anemia in mtDNA-mutator mice. These findings highlight a pathological feedback loop that explains how dysfunctional mitochondria can escape autophagy-mediated degradation and propagate in cells predisposed to somatic mtDNA mutations, leading to disease.
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Project description:Pseudomonas aeruginosa evolving in the cystic fibrosis (CF) lung encounters selection via iron-limitation, antibiotics, immune system effectors and other microbes. Standing genetic variation, which depends on rates of horizontal gene transfer (HGT) and mutation supply, controls response to challenges. HGT may increase if new clones successfully invade, while mutator strains increase new mutations. We sought to ascertain genomic signatures of invasion and whether, in the absence of novel invasion, mutator-containing P. aeruginosa populations from chronically infected CF lung are more genetically variable than nonmutator populations. Forty-nine strains from 14 patients treated over three years at Necker Children’s Hospital in Paris were phenotyped for antibiotic resistance, mucoidy and mutator status, and then genotyped by rep-PCR, PFGE and MLST analysis. Overall, strains exhibited greater genetic similarity within patients than among patients, with initial and terminal clones differing markedly between series, indicating unrelated clones independently established infections and resisted invasions that might enlarge genetic variation by sexual recombination. Mutator series were more likely to be multiply antibiotic-resistant, but were no more genetically variable at the single nucleotide level. DNA microarray analyses of bacterial genomes in two longitudinal series of equal duration, one containing and one lacking mutators, revealed both series conspicuously lack genes encoding proteins involved in attachment, motility and amino acid biosynthesis. The mutator series also contained fewer genes hybridizing to canonical PAO1 genome sequences. These data suggest genetic variation arising from mutators may be limited in scope, transient in nature or not easily resolved by fingerprinting, MLST or comparative genomic analyses.
2011-10-31 | GSE25481 | GEO
Project description:microarray experiment to test the gene expression in long term lines of mutator and non-mutator yeast. Here we use an experimental evolution approach to investigate the conditions required for evolution of a reduction in mutation rate and the mechanisms by which populations tolerate the accumulation of deleterious mutations. We find that after ~6700 generations four out of eight experimental mutator lines had evolved a decreased mutation rate. 2 condition experiment, derived experimental evolution strains compared to their ancestor strain. We compared the expression profile of one of the mutator lines (m8) after 6700 generations with its mutator ancestor, and as a control, an evolved non mutator after 6700 generations was compared to to its non-mutator ancestor. In order to prepare cells for expression microarray, glass tubes containing 3 ml of YPD were inoculated from overnight cultures, and grown until the OD600 was approximately 0.3.
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Project description:piRNAs play a critical role in the regulation of transposons and other germline genes. In Caenorhabditis elegans, silencing of piRNA target genes is mediated by the Mutator complex, which synthesizes high levels of siRNAs through the activity of an RNA-dependent RNA polymerase. However, how mRNAs recognized by the piRNA pathway are handed off to the Mutator pathway is unclear. Here, we identify the Tudor domain-containing protein, SIMR-1, as a key mediator of this handoff. Interestingly, SIMR-1 also localizes to distinct subcellular foci adjacent to P granules and Mutator foci, two phase-separated condensates that are the sites of piRNA-dependent mRNA recognition and Mutator complex-dependent siRNA amplification, respectively. Thus, our data suggests a role for multiple perinuclear condensates in organizing the piRNA pathway and promoting silencing by the Mutator complex.
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Project description:Pseudomonas aeruginosa evolving in the cystic fibrosis (CF) lung encounters selection via iron-limitation, antibiotics, immune system effectors and other microbes. Standing genetic variation, which depends on rates of horizontal gene transfer (HGT) and mutation supply, controls response to challenges. HGT may increase if new clones successfully invade, while mutator strains increase new mutations. We sought to ascertain genomic signatures of invasion and whether, in the absence of novel invasion, mutator-containing P. aeruginosa populations from chronically infected CF lung are more genetically variable than nonmutator populations. Forty-nine strains from 14 patients treated over three years at Necker Children’s Hospital in Paris were phenotyped for antibiotic resistance, mucoidy and mutator status, and then genotyped by rep-PCR, PFGE and MLST analysis. Overall, strains exhibited greater genetic similarity within patients than among patients, with initial and terminal clones differing markedly between series, indicating unrelated clones independently established infections and resisted invasions that might enlarge genetic variation by sexual recombination. Mutator series were more likely to be multiply antibiotic-resistant, but were no more genetically variable at the single nucleotide level. DNA microarray analyses of bacterial genomes in two longitudinal series of equal duration, one containing and one lacking mutators, revealed both series conspicuously lack genes encoding proteins involved in attachment, motility and amino acid biosynthesis. The mutator series also contained fewer genes hybridizing to canonical PAO1 genome sequences. These data suggest genetic variation arising from mutators may be limited in scope, transient in nature or not easily resolved by fingerprinting, MLST or comparative genomic analyses. Clinical P. aeruginosa hypermutator and nonhypermutator lineages from CF lung. Array-based genome hybridization.
2011-10-31 | E-GEOD-25481 | biostudies-arrayexpress