Chromosome X Dosage Modulates Development of Aneuploidy in Genetically Diverse Mouse Embryonic Stem Cells [D0_scRNA-seq]
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PROVIDER: PRJNA1213835 | ENA |
REPOSITORIES: ENA
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Project description:Chromosome X Dosage Modulates Development of Aneuploidy in Genetically Diverse Mouse Embryonic Stem Cells [C3H_scRNA-seq]
| PRJNA1214296 | ENA
Project description:The genetic integrity of pluripotent stem cells (PSC) is integral to their applications in research and therapy, but it is compromised by frequent development of copy number variations. Little is known about the basis of the variable genomic integrity among different PSC lines. Here we identify aneuploidies using RNA-seq and proteomics data from a panel of mouse embryonic stem cell (mESC) lines derived from 170 Diversity Outbred mice. We identified 62 lines with detectable aneuploid subpopulations and a subset of originally XX lines that lost one Chromosome X (XO). Strikingly, a much lower proportion of XX lines were aneuploid, compared to XY or XO lines. Two single-cell RNA-seq data sets demonstrated that aneuploid XY DO mESC also show lower Chromosome X gene expression and that XY mESC accumulate higher aneuploid proportions in culture than isogenic XX lines. Possible mechanisms for this protective effect of X chromosome dosage include our discovery that the lines with two active X Chromosomes have a higher expression of 2-cell-like state genes, and differential expression of X-linked tumor suppressor genes associated with DNA damage response.
2025-01-22 | GSE287717 | GEO
Project description:The genetic integrity of pluripotent stem cells (PSC) is integral to their applications in research and therapy, but it is compromised by frequent development of copy number variations. Little is known about the basis of the variable genomic integrity among different PSC lines. Here we identify aneuploidies using RNA-seq and proteomics data from a panel of mouse embryonic stem cell (mESC) lines derived from 170 Diversity Outbred mice. We identified 62 lines with detectable aneuploid subpopulations and a subset of originally XX lines that lost one Chromosome X (XO). Strikingly, a much lower proportion of XX lines were aneuploid, compared to XY or XO lines. Two single-cell RNA-seq data sets demonstrated that aneuploid XY DO mESC also show lower Chromosome X gene expression and that XY mESC accumulate higher aneuploid proportions in culture than isogenic XX lines. Possible mechanisms for this protective effect of X chromosome dosage include our discovery that the lines with two active X Chromosomes have a higher expression of 2-cell-like state genes, and differential expression of X-linked tumor suppressor genes associated with DNA damage response.
2025-01-22 | GSE287621 | GEO
Project description:Aneuploidy, an imbalance in chromosome copy numbers, causes genetic disorders, and drives cancer progression, drug tolerance, and antimicrobial resistance. While aneuploidy can confer stress resistance, it is not well understood how cells overcome the fitness burden caused by aberrant chromosomal copy numbers. Studies using both systematically generated and natural aneuploid yeasts triggered an intense debate about the role of dosage compensation, concluding that aneuploidy is transmitted to the transcriptome and proteome without significant buffering at the chromosome-wide level, and is, at least in lab strains, associated with significant fitness costs. Conversely, systematic sequencing and phenotyping of large collections of natural isolates revealed that aneuploidy is frequent and has few, if any, fitness costs in nature. To address these discrepant findings, we developed a platform that yields highly precise proteomic measurements across large numbers of genetically diverse samples and applied it to natural isolates collected as part of the 1011 genomes project (Peter, J. et al, 2018). For 613 of the isolates, we were able to match the proteomes to their corresponding transcriptomes and genomes, subsequently quantifying the effect of aneuploidy on gene expression by comparing 95 aneuploid with 518 euploid strains. We find, as in previous studies, that aneuploid gene dosage is not buffered chromosome-wide at the transcriptome level. Importantly, in the proteome, we detect an attenuation of aneuploidy by about 25% below the aneuploid gene dosage in natural yeast isolates. Furthermore, this chromosome-wide dosage compensation is associated with the ubiquitin-proteasome system (UPS), which is expressed at higher levels and has increased activity across natural aneuploid strains. Thus, through systematic exploration of the species-wide diversity of the yeast proteome, we shed light on a long-standing debate about the biology of aneuploids, revealing that aneuploidy tolerance is mediated through chromosome-wide dosage compensation at the proteome level.
| MSV000090435 | MassIVE
Project description:<p>Aneuploidy causes system-wide disruptions in the stochiometric balances of transcripts, proteins, and metabolites, often resulting in detrimental effects for the organism. The protozoan parasite Leishmania has an unusually high tolerance for aneuploidy, but the molecular and functional consequences for the pathogen remain poorly understood. Here, we addressed this question in vitro and present the first integrated analysis of the genome, transcriptome, proteome, and metabolome of highly aneuploid Leishmania donovani strains. Our analyses unambiguously establish that aneuploidy in Leishmania proportionally impacts the average transcript- and protein abundance levels of affected chromosomes, ultimately correlating with the degree of metabolic differences between strains. This proportionality was present in both proliferative and non-proliferative in vitro promastigotes. However, protein complex subunits and non-cytoplasmic proteins, showed dosage compensation, responding less or even not at all to aneuploidy-induced dosage changes. In contrast to other Eukaryotes, we did not observe the widespread regulation at the transcript level that typically modulates some of the negative effects of aneuploidy. Further, the majority of differentially expressed proteins between aneuploid strains were encoded by non-aneuploid chromosomes and were not driven by a significant underlying transcript change, suggesting that aneuploidy is accompanied by extensive post-transcriptional protein-level modulation. This makes Leishmania a unique Eukaryotic model for elucidating post-transcriptional protein-abundance modulation in the context of aneuploidy.</p><p><br></p><p><strong>Data availability:</strong></p><p>Proteomic data associated with this study are available in the PRIDE repository: accession number <a href='https://www.ebi.ac.uk/pride/archive/projects/PXD028521' rel='noopener noreferrer' target='_blank'>PXD028521</a>.</p>
2022-09-19 | MTBLS1612 | MetaboLights
Project description:Aneuploidy, the state in which an organism’s genome contains one or more missing or additional chromosomes, often causes widespread genotypic and phenotypic effects. Most often, aneuploidies are deleterious; the most common examples in humans being Down’s syndrome (Trisomy 21) and Turner’s syndrome (monosomy X). However, aneuploidy is surprisingly common in wild yeast populations. In recent years, there has been debate as to whether yeast contain an innate dosage compensation response on the whole-genome level, or if these natural isolates are robust to aneuploidy without such a mechanism. In this study, we tested for differential gene expression in 20 aneuploid and 18 euploid lines of yeast from two previous mutation accumulation experiments, where selection was low and therefore aneuploidies arose spontaneously. We found no evidence for whole-chromosome dosage compensation in aneuploid yeast but did find some evidence for attenuation of expression on a gene-by-gene basis. We additionally found that aneuploidy has no effect on the expression of the rest of the genome (i.e. “trans” genes), and that very few mutually exclusive aneuploid lines shared differentially expressed genes. However, we found a small common differential expression response in the euploid lines, suggesting an effect of mutation accumulation on gene expression. Our findings contribute to our understanding of aneuploidy in yeast and support the hypothesis that there is no innate dosage compensation mechanism at the whole-chromosome level.
2021-03-11 | GSE168674 | GEO
Project description:Aneuploidy results in decreased cellular fitness in many different species and model systems. However, aneuploidy is commonly found in cancer cells and often correlates with aggressive growth and poor prognosis, suggesting that the impact of aneuploidy on cellular fitness is context dependent. The BRG1 (SMARCA4) subunit of the SWI/SNF chromatin remodelling complex is a tumour suppressor that is frequently lost in cancer cells. Here, we used a chromosomally stable cell line to test the effect of BRG1 loss on the evolution of aneuploidy. We find that BRG1 deletion leads to an initial loss of fitness in this cell line that improves over time. The improved fitness correlates with a gain of extra copies of chromosome 18. Notably, changes in pathways that are known to promote tolerance to aneuploidy are evident immediately upon loss of BRG1, providing an environment where karyotype changes associated with a fitness advantage can be explored. At least in some genetic backgrounds, therefore, loss of the SWI/SNF complex can contribute to tumourigenesis through tolerance of aneuploidy.
2022-03-23 | PXD014954 | Pride
Project description:Chromosomal instability (CIN) is thought to be a source of mutability in human cancer. However, CIN is highly deleterious for the cell, and the resulting aneuploidy induces metabolic stress and compromises cell fitness. Here we utilized the X-chromosome dosage compensation mechanism and changes in X-chromosome number to demonstrate in Drosophila epithelial cells the causal relationship between CIN, aneuploidy, gene dosage imbalance and tumorigenesis. Whereas the harmful effects of CIN can be buffered by resetting the X-chromosome dosage compensation to compensate for changes in X-chromosome number, interfering with the mechanisms of dosage compensation suffices to induce tumorigenesis. In addition, multiple mechanisms buffer the deleterious effects of CIN including DNA-damage repair, activation of the p38 signalling pathway, and induction of cytokine expression to promote compensatory cell proliferation. These data reveal a key role of gene dosage imbalances to CIN-induced programmed cell death and tumorigenesis and the existence of robust compensatory mechanisms.
2016-05-23 | GSE71242 | GEO
Project description:Host-pathogen genetic interactions underlie tuberculosis susceptibility in genetically diverse mice
| PRJNA689305 | ENA
Project description:Aneuploidy, or an aberrant karyotype, results in developmental disabilities and has been implicated in tumorigenesis. However, the causes of aneuploidy-induced phenotypes and the consequences of aneuploidy on cell physiology remain poorly understood. We have performed a meta-analysis on gene expression data from aneuploid cells in diverse organisms, including yeast, plants, mice, and humans. We found highly-related gene expression patterns that are conserved between species: genes that were involved in the response to stress were consistently upregulated, while genes associated with the cell cycle and cell proliferation were downregulated in aneuploid cells. Within species, different aneuploidies induced similar changes in gene expression, independent of the specific chromosomal aberrations. Taken together, our results demonstrate that aneuploidies of different chromosomes and in different organisms impact similar cellular pathways and cause a stereotypical anti-proliferative response that must be overcome prior to transformation. These experiments are two-color hybridizations of RNA isolated from aneuploid samples vs matched wt cells, all grown to midlog phase.
2012-06-28 | E-GEOD-35853 | biostudies-arrayexpress