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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of mouse embryonic fibroblasts (MEFs) trisomic for chromosomes 1, 13, 16 and 19

ABSTRACT: Aneuploidy, an incorrect chromosome number, is the leading cause of miscarriages and mental retardation in humans and is a hallmark of cancer. We examined the effects of aneuploidy on primary mouse cells by generating a series of cell lines that carry an extra copy of one of four mouse chromosomes. In all four trisomic lines proliferation was impaired and metabolic properties were altered. Immortalization, the acquisition of the ability to proliferate indefinitely, was also affected by the presence of an additional chromosome, with some chromosomes inhibiting immortalization while others accelerating the process. Our data indicate that aneuploidy decreases not only organismal but also cellular fitness and elicits traits that are shared between different aneuploid cells. Experiment Overall Design: The mRNAs from 9 different mouse embryo fibroblast (MEF) lines with a normal complement of chromosomes were compared to mRNAs from 1 MEF line with three copies of chromosome 1, 4 MEF lines with three copies of chrmosome 13, 3 MEF lines with three copies of chromosome 16 and 1 MEF line with three copies of chromosome 19.

ORGANISM(S): Mus musculus

SUBMITTER: Charles Arthur Whittaker

PROVIDER: E-GEOD-12501 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Gene Expression in MEFs Trisomic for Chromosomes 1, 13, 16 and 19

Project description:Aneuploidy, an incorrect chromosome number, is the leading cause of miscarriages and mental retardation in humans and is a hallmark of cancer. We examined the effects of aneuploidy on primary mouse cells by generating a series of cell lines that carry an extra copy of one of four mouse chromosomes. In all four trisomic lines proliferation was impaired and metabolic properties were altered. Immortalization, the acquisition of the ability to proliferate indefinitely, was also affected by the presence of an additional chromosome, with some chromosomes inhibiting immortalization while others accelerating the process. Our data indicate that aneuploidy decreases not only organismal but also cellular fitness and elicits traits that are shared between different aneuploid cells. Keywords: cell type comparison

2008-11-05 | GSE12501 | GEO

Gene expression in mouse embryonic stem cells trisomic for chromosome 6, 8, 11 and 15

Project description:Aneuploidy, an uneven number of chromosomes, leads to severe developmental defects in mammals and is also a hallmark of cancer. However, whether aneuploidy is a driving cause or a consequence of tumor formation remains controversial. Paradoxically, existing studies based on aneuploid yeast and mouse fibroblasts have shown that aneuploidy is usually detrimental to cellular fitness. Here, we examined the effects of aneuploidy on mouse embryonic stem cells. Using a novel genetic scheme, we generated a series of aneuploid cell lines that each carries an extra copy of single chromosomes and then characterized the traits shared by these cell lines. All the aneuploid cell lines had rapid proliferation rates and enhanced colony formation efficiencies. They were less dependent on growth factors for self-renewal and showed a reduced capacity to differentiate in vitro. Moreover, xenografted aneuploid stem cells formed teratomas more efficiently, with features of neoplastic progression. These findings demonstrate that aneuploidy enhances the self-renewal capacities of stem cells and reduces their differentiation abilities.

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CGH analysis of mouse embryonic stem cells trisomic for chromosome 6, 8, 11,12 and 15

2017-02-09 | GSE55500 | GEO

The effect of trisomic chromosomes on spatial genome organization and global transcription in embryonic stem cells

Project description:Aneuploidy frequently occurs in cancer and developmental diseases such as Down syndrome, with its functional consequences implicated in dosage effects on gene expression and global perturbation of stress response and cell proliferation pathways. However, how aneuploidy affects spatial genome organization remains less understood. In this study, we addressed this question by utilizing the previously established isogenic wild-type (WT) and trisomic mouse embryonic stem cells (mESCs). We employed a combination of Hi-C, RNA-seq, chromosome painting and nascent RNA imaging technologies to compare the spatial genome structures and gene transcription among these cells. We found that trisomy has little effect on spatial genome organization at the level of A/B compartment or topologically associating domain (TAD). Inter-chromosomal interactions are associated with chromosome regions with high gene density, active histone modifications and high transcription levels, which are confirmed by imaging. Imaging also revealed contracted chromosome volume and weakened transcriptional activity for trisomic chromosomes, suggesting potential implications for the transcriptional output of these chromosomes. Our data resources and findings may contribute to a better understanding of the consequences of aneuploidy from the angle of spatial genome organization.

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Dosage compensation can buffer copy-number variation in wild yeast

Project description:We show that aneuploidy is common in wild isolates of yeast, which are inherently tolerant to chromosome amplification and down-regulate expression at 40% of amplified genes. To dissect the mechanism of this dosage response, we generated isogenic strain panels in which diploid cells carried either two, three, or four copies of the affected chromosomes. Using a mixture of linear regression (MLR) model to classify genes, we find that expression is actively down regulated in proportion to increased gene copy at up to 30% of genes. Genes subject to dosage control are under higher expression constraint – but show elevated rates of gene amplification – in wild populations, suggesting that dosage compensation buffers copy number variation (CNV) at toxic genes RNA-seq and transcriptome analysis of S. cerevisiae natural isolates having aneuploidy. Technical triplicate was performed for isogenic diploid strains having 2, 3 and 4 copies of a given chromosome (strain panels), while technical duplicate or singulate was performed on all other aneuploids.

2015-05-08 | E-GEOD-61532 | biostudies-arrayexpress

Transcription profiling of Drosophila deficiency hemizygotes and a duplication hemizygote reveals buffering of segmental and chromosomal aneuploidies in Drosophila melanogaster

Project description:Chromosomal instability which involves deletion and duplication of chromosomes or chromosome parts is a common feature of cancers, and deficiency screens are commonly used as a method to find genes involved in different biological pathways. Still, how gene expression from whole chromosomes or large chromosomal domains is affected by deficiencies, duplications or chromosome loss is largely unknown. Using expression microarrays of deficiency hemizygotes and a duplication hemizygote we show that expressed genes are significantly buffered when present in a deficiency hemizygote and that the buffering effect is general and not mainly caused by feedback regulation of individual genes. Differentially expressed genes are in general better buffered than ubiquitously expressed genes when present in one copy. When present in three copies, differentially expressed genes are in general less buffered than ubiquitously expressed genes. Furthermore, we show that the 4th chromosome is compensated in response to dose differences. Our results suggest that general mechanisms exist to stimulate and to repress gene expression of aneuploidy regions and on the 4th chromosome this compensation is mediated by POF (Painting of Fourth). Experiment Overall Design: We prepared total RNA from flies heterozygous for three different deletions, Df(2L)J-H, Df (2L)ED4470, Df(2L)ED4651, flies heterozygous for the duplication Dp(2;2)Cam3 and flies with only one chromosome 4, or three copies of the 4th chromosome, as well as from wild type control flies. Three biological replicates of all genotypes were prepared.

2009-04-03 | E-GEOD-14517 | biostudies-arrayexpress

Loss of the SUMO Protease Ulp2 Triggers a Specific Multi-Chromosome Aneuploidy

Project description:Post-translational protein modification by the small ubiquitin-related modifier (SUMO) protein regulates numerous cellular pathways, including transcription, cell division and genome maintenance. The SUMO protease Ulp2 modulates many of these SUMO-dependent processes in budding yeast. To investigate changes to the transcriptome of cells lacking Ulp2, whole-genome RNA sequencing (RNA-seq) was employed. Unexpectedly, ulp2Δ cells display a general two-fold increase in transcript levels across two particular chromosomes, Chromosome I (ChrI) and Chromosome XII (ChrXII). Quantification of relative DNA levels showed that ChrI and ChrXII are present at twice their normal copy number in ulp2Δ cells. This double disomy occurs in mutants in multiple genetic backgrounds and does not require passage through meiosis. An abnormal number of chromosomes in a cell, termed aneuploidy, is usually deleterious. However, development of specific aneuploidies allows rapid adaptation to cellular stresses in yeast and other species, and aneuploidy characterizes most tumors. Extra copies of ChrI and ChrXII appear quickly following loss of active Ulp2, suggesting aneuploidy is an adaptive mechanism in cells lacking the functional SUMO protease. The specific aneuploidy in ulp2Δ cells highlights a unique example of a homogeneous, multi-chromosome aneuploidy in response to mutation of a single gene.

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Buffering and proteolysis are induced upon segmental haploidy in Drosophila melanogaster.

Project description:Aneuploidy, i.e., variation in the number of individual chromosomes (chromosomal aneuploidy) or chromosome segment (segmental aneuploidy) is associated with developmental abnormalities and reduced fitness in all species examined, is the leading cause of miscarriages and mental retardations and a hallmark of cancer. Despite their documented importance in disease the effects of aneuploidies on the transcriptome remains largely unknown. Here we have examined the expression output in seven deficiency heterozygotes as single deficiencies and in all pairwise combinations. The results show that genes in one copy are buffered, i.e., are expressed above the expected 50% expression level compared to wild type and the buffering is general and not influenced by additional haploid regions. Long genes are significantly better buffered than short genes and our analysis suggests that gene length is the primary determinant for the degree of buffering. For short genes the degree of buffering depends on expression level and expression pattern. Furthermore, the results show that in deficiency heterozygotes the expression of genes involved in proteolysis is enhanced and negatively correlates with the degree of buffering. Our results suggest that proteolysis is a general response induced by aneuploidy. We prepared total RNA from flies heterozygous for seven different deletions, Df(3R)ED10953, Df(2L)ED4559, Df(2R)ED1770, Df(2R)ED1612, Df(2L)ED3, Df(3R)ED5071 or Df(3R)ED7665 in two or three single biological replicates or in pairwise combinations, as well as from six biological replicates of wild type control flies.

2012-04-04 | E-GEOD-34400 | biostudies-arrayexpress

Genome-wide transcriptional response to random aneuploidy in human cells

Project description:Previous studies on transcriptional response to aneuploidy have focused on comparing model cell lines harbouring defined aneuploidy (specific chromosomes) with their parental diploid cell lines. However, the majority of tumours are composed of cancer cells with complex karyotypes (diverse chromosome assortment). Despite this fact, proven functions of random aneuploidies in promoting tumourigenesis are lacking. This prompted us to investigate the transcriptional response to heterogenous cell populations with discernible random aneuploidies.

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Transcription profiling of A.thaliana to determine the ffect of aneuplody extra copy of chromosome 5

Project description:Effects of aneuploidy on gene expression in Arabidopsis thaliana containing extra copies of chromosome 5.

2008-09-01 | E-MEXP-1454 | biostudies-arrayexpress