Association of aneuploidy with centromeric features
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE132193 | GEO | 2019/11/26
REPOSITORIES: GEO
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Project description:Association of aneuploidy with centromeric features
| PRJNA546288 | ENA
Project description:Aneuploidy, a hallmark of cancer, often arises from whole-chromosomal instability (W-CIN). Many cancers exhibiting W-CIN, however, show no direct insult to the mitotic proteins that ensure proper segregation of chromosomes. This has stimulated interest in identifying defects in non-mitotic processes that might disrupt chromosome behavior in mitosis. Here we show in Saccharomyces cerevisiae that transient re-replication of centromeric DNA, due to deregulation of replication initiation proteins, greatly induces aneuploidy of the rereplicated chromosome. Some of this aneuploidy appears to arise from simple missegregation of both sister chromatids to one daughter cell, indicating that centromeric re-replication can disrupt proper centromere function during mitosis. Another source of aneuploidy appears to be the generation of an extra sister chromatid via homologous recombination, suggesting that centromeric rereplication can trigger breakage and repair events that expand chromosome numbers while preserving chromosome structure. Given the emerging connections between the deregulation of replication initiation proteins and oncogenesis, our findings offer the possibility of a new non-mitotic source of aneuploidy that may be relevant to cancer.
2014-07-25 | GSE55641 | GEO
Project description:Centromeres play an essential role in cell division by specifying the site of kinetochore formation on each chromosome so that chromosomes can attach to the mitotic spindle for segregation. Centromeres are defined epigenetically by the histone H3 variant CEntromere Protein A (CENP-A). Dividing cells maintain the centromere by depositing new CENP-A each cell cycle to replenish CENP-A diluted by replication. The CENP-A nucleosome serves as the primary signal to the machinery responsible for its replenishment. Vertebrate centromeres are frequently built on repetitive sequences organized in tandem arrays. Repetitive centromeric DNA has been suggested to play a role in centromere maintenance and in de novo centromere formation, but this has been difficult to dissect because of the difficulty in manipulating centromere in cells. Extracts from Xenopus laevis eggs are able to assemble centromeres and kinetochores in vitro and thus provide a useful system for studying the role of centromeric DNA in centromere formation. However centromeric sequences in X. laevis have not been extensively characterized.. In this study we characterize repeat sequences found at X. laevis centromeres. We utilize a k-mer based approach in order to uncover the previously unknown diversity of X. laevis centromeric sequences. We validate centromere localization of repeat sequences by in situ hybridization and identify the location of the centromeric repetitive array on each chromosome by mapping the distribution of centromere enriched k-mers on the Xenopus genome. Our identification of X. laevis centromere sequences enables previously unapproachable genomic studies of centromeres. The k-mer based approach that we used to investigate centromeric repetitive DNA is suitable for the analysis of other repetitive sequences found across the genome or the study of repeats in other organisms.
2020-06-24 | GSE153058 | GEO
Project description:Aneuploidy, the presence of chromosome gains or losses, is a hallmark of cancer and congenital syndromes. Here, we describe KaryoCreate (Karyotype CRISPR Engineered Aneuploidy Technology), a system that enables generation of chromosome-specific aneuploidies by co-expression of a sgRNA targeting chromosome-specific CENPA-binding ɑ-satellite repeats together with dCas9 fused to a mutant form of KNL1. We designed unique and highly specific sgRNAs for 19 out of 24 chromosomes. Expression of these sgRNAs with KNL1Mut-dCas9 leads to missegregation and induction of gains or losses of the targeted chromosome in cellular progeny with an average efficiency of 8% and 12% for gains and losses, respectively (up to 20%), tested and validated across 9 chromosomes. Using KaryoCreate in colon epithelial cells, we show that chromosome 18q loss, a frequent occurrence in gastrointestinal cancers, promotes resistance to TGFβ, likely due to synergistic hemizygous deletion of multiple genes. Altogether, we describe a novel technology to create and study chromosome missegregation and aneuploidy in the context of cancer and beyond.
2023-08-14 | GSE217325 | GEO
Project description:Aneuploidy, the presence of chromosome gains or losses, is a hallmark of cancer and congenital syndromes. Here, we describe KaryoCreate (Karyotype CRISPR Engineered Aneuploidy Technology), a system that enables generation of chromosome-specific aneuploidies by co-expression of a sgRNA targeting chromosome-specific CENPA-binding ɑ-satellite repeats together with dCas9 fused to a mutant form of KNL1. We designed unique and highly specific sgRNAs for 19 out of 24 chromosomes. Expression of these sgRNAs with KNL1Mut-dCas9 leads to missegregation and induction of gains or losses of the targeted chromosome in cellular progeny with an average efficiency of 8% and 12% for gains and losses, respectively (up to 20%), tested and validated across 9 chromosomes. Using KaryoCreate in colon epithelial cells, we show that chromosome 18q loss, a frequent occurrence in gastrointestinal cancers, promotes resistance to TGFβ, likely due to synergistic hemizygous deletion of multiple genes. Altogether, we describe a novel technology to create and study chromosome missegregation and aneuploidy in the context of cancer and beyond.
2023-08-14 | GSE215842 | GEO
Project description:Functional centromeres are essential for proper cell division. Centromeres are established largely by epigenetic processes resulting in incorporation of the histone H3 variant CENP-A. Here, we demonstrate the direct involvement of H2B monoubiquitination, mediated by RNF20 in humans or Brl1 in Schizosaccharomyces pombe, in centromeric chromatin maintenance. Monoubiquinated H2B (H2Bub1) is needed for this maintenance, promoting noncoding transcription, centromere integrity and accurate chromosomal segregation. A transient pulse of centromeric H2Bub1 leads to RNA polymerase II–mediated transcription of the centromere’s central domain, coupled to decreased H3 stability. H2Bub1-deficient cells have centromere cores that, despite their intact centromeric heterochromatin barriers, exhibit characteristics of heterochromatin, such as silencing histone modifications, reduced nucleosome turnover and reduced levels of transcription. In the H2Bub1-deficient cells, centromere functionality is hampered, thus resulting in unequal chromosome segregation. Therefore, centromeric H2Bub1 is essential for maintaining active centromeric chromatin.
2014-01-29 | GSE49874 | GEO
Project description:Centromeres typically contain repeat sequences, but centromere function does not necessarily depend on these sequences. In aneuploid wheat (Triticum aestivum) and wheat distant hybridization offspring, we found functional centromeres with dramatic changes to centromeric retrotransposon of wheat (CRW) sequences. CRW sequences were greatly reduced in the ditelosomic lines 1BS, 5DS, 5DL, and a wheat-Thinopyrum elongatum addition line. CRWs were completely lost in the ditelosomic line 4DS, but a 994 kb ectopic genomic DNA sequence was involved in de novo centromere formation on the 4DS chromosome. In addition, two ectopic sequences were incorporated in a de novo centromere in a wheat-Th. intermedium addition line. Centromeric sequences were also expanded to the chromosome arm in wide hybridizations. Stable alien chromosomes with two and three regions containing centromeric sequences were found in wheat-Th. elongatum hybrid derivatives, but only one is functional. In wheat-rye (Secale cereale) hybrids, rye centromere specific sequences spread to the chromosome arm and may cause centromere expansion. Thus, distant wheat hybridizations cause frequent and significant changes to the centromere via centromere misdivision, which may affect retention or loss of alien chromosomes in hybrids.
2016-04-02 | GSE63752 | GEO
Project description:Centromeres typically contain repeat sequences, but centromere function does not necessarily depend on these sequences. In aneuploid wheat (Triticum aestivum) and wheat distant hybridization offspring, we found functional centromeres with dramatic changes to centromeric retrotransposon of wheat (CRW) sequences. CRW sequences were greatly reduced in the ditelosomic lines 1BS, 5DS, 5DL, and a wheat-Thinopyrum elongatum addition line. CRWs were completely lost in the ditelosomic line 4DS, but a 994 kb ectopic genomic DNA sequence was involved in de novo centromere formation on the 4DS chromosome. In addition, two ectopic sequences were incorporated in a de novo centromere in a wheat-Th. intermedium addition line. Centromeric sequences were also expanded to the chromosome arm in wide hybridizations. Stable alien chromosomes with two and three regions containing centromeric sequences were found in wheat-Th. elongatum hybrid derivatives, but only one is functional. In wheat-rye (Secale cereale) hybrids, rye centromere specific sequences spread to the chromosome arm and may cause centromere expansion. Thus, distant wheat hybridizations cause frequent and significant changes to the centromere via centromere misdivision, which may affect retention or loss of alien chromosomes in hybrids. ChIP-seq was carried out with anti-CENH3 antibody using material 4DS and control (Chinese Spring, CS as short).
2016-04-02 | E-GEOD-63752 | biostudies-arrayexpress
Project description:The centromere is the genetic locus that organizes the proteinaceous kinetochore and is responsible for attachment of the chromosome to the spindle at mitosis and meiosis. In most eukaryotes, the centromere consists of highly repetitive DNA sequences that are occupied by nucleosomes containing the CenH3 histone variant, whereas in budding yeast, an ~120-bp Centromere DNA Element (CDE) that is sufficient for centromere function is occupied by a single right-handed CenH3 (Cse4) nucleosome. However, these in vivo observations are inconsistent with in vitro evidence for left-handed octameric CenH3 nucleosomes. To help resolve these inconsistencies, we characterized yeast centromeric chromatin at single base-pair resolution. Intact particles containing both Cse4 and H2A are precisely protected from micrococcal nuclease over the entire CDE of all 16 yeast centromeres in both solubilized chromatin and the insoluble kinetochore. Small DNA-binding proteins protect CDEI and CDEIII and delimit the centromeric nucleosome to the ~80-bp CDEII, only enough for a single DNA wrap. As expected for a tripartite organization of centromeric chromatin, loss of Cbf1 protein, which binds to CDEI, both reduces the size of the centromere-protected region and shifts its location towards CDEIII. Surprisingly, Cse4 overproduction caused genome-wide misincorporation of non-functional CenH3-containing nucleosomes that protect ~135 base pairs and are preferentially enriched at sites of high nucleosome turnover. Our detection of two forms of CenH3 nucleosomes in the yeast genome, a singly wrapped particle at the functional centromere and octamer-sized particles on chromosome arms, reconcile seemingly conflicting in vivo and in vitro observations.
2011-12-07 | GSE28298 | GEO
Project description:Eukaryotes have evolved elaborate mechanisms to ensure that chromosomes segregate with high fidelity during mitosis and meiosis, and yet specific aneuploidies can be adaptive during environmental stress. Here, we identify a chromatin-based system for inducible aneuploidy in a human pathogen. Candida albicans utilizes chromosome missegregation to acquire resistance to antifungal drugs and for ploidy reduction after mating. We discovered that the ancestor of C. albicans and two related pathogens evolved a variant of histone H2A that lacks the conserved phosphorylation site for Bub1 kinase, a key regulator of chromosome segregation. Using engineered strains, we show that expression of this variant controls the rates of aneuploidy and antibiotic resistance in this species. Moreover, whole genome chromatin precipitation analysis reveals that CENP-A/Cse4, the histone H3 that specifies centromeres, is depleted from tetraploid mating products and virtually eliminated from cells exposed to aneuploidy-promoting cues. Thus, changes in chromatin regulation can confer the capacity for rapid evolution in eukaryotes.
2019-05-23 | GSE122037 | GEO