Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Chromatin rewiring mediates programmed evolvability via aneuploidy

ABSTRACT: 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.

ORGANISM(S): Candida albicans

PROVIDER: GSE122037 | GEO | 2019/05/23

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Deposition of centromeric histone H3 variant CENP-A/Cse4 into chromatin is facilitated by its C-terminal sumoylation

Project description:Centromeric localization of CENP-A (Cse4 in S. cerevisiae, CID in flies, CENP-A in humans) is essential for faithful chromosome segregation. Overexpression of CENP-A leads to its mislocalization and contributes to aneuploidy in yeast, flies, humans and is proposed to promote tumorigenesis in human cancers. Hence, defining molecular mechanisms that promote or prevent mislocalization of CENP-A is an area of active investigation. In budding yeast, evolutionarily conserved histone chaperones Scm3 and chromatin assembly factor-1 (CAF-1) promote localization of Cse4 to centromeric and non-centromeric regions, respectively. Ubiquitin ligases such as Psh1 and Slx5 and histone chaperones (HIR complex) regulate proteolysis of overexpressed Cse4 and prevent its mislocalization to non-centromeric regions. In this study, we have identified sumoylation sites lysine (K) 215/216 in the C-terminus of Cse4 and shown that sumoylation of Cse4 K215/216 facilitates its genome-wide deposition into chromatin when overexpressed. Our results showed reduced levels of sumoylation of mutant Cse4 K215/216R/A (K changed to arginine (R) or alanine (A)) and reduced interaction of mutant Cse4 K215/215R/A with Scm3 and CAF-1 when compared to wild type Cse4. Consistent with these results, levels of Cse4 K215/216R/A in the chromatin fraction at centromeric and non-centromeric regions were reduced. Furthermore, in contrast to GAL-CSE4 which exhibits Synthetic Dosage Lethality (SDL) in psh1Æ, slx5Æ, and hir2Æ strains, GAL-cse4 K215/216R does not exhibit SDL in these strains. Taken together, our results identify and define a role for C-terminal sumoylation of Cse4 for its incorporation into chromatin.

2020-02-21 | GSE145602 | GEO

Centromere-Like Regions in Budding Yeast

Project description:Accurate chromosome segregation requires centromeres (CENs), the chromosomal sites where kinetochores form, to bridge DNA and attach to microtubules. In contrast to most eukaryotes, Saccharomyces cerevisiae possesses sequence-defined point centromeres. Chromatin immunoprecipitation followed by sequencing (ChIP-Seq) of four kinetochore components reveals regions of overlapping, extra-centromeric protein localization upon overproduction of the centromeric histone, Cse4 (CENP-A or CenH3). These identified sequences enhance proper plasmid and chromosome segregation, and are termed Centromere-like Regions (CLRs). CLRs form in close proximity to S. cerevisiae CENs and share characteristics typical of point and regional centromeres. CLR sequences are conserved among related budding yeasts, suggesting a role in vivo. These studies provide new insights into the origin and evolution of centromeres. ChIP-Seq analysis of the kinetochore components Cse4, Mif2, Ndc10 and Ndc80 in budding yeast strains (Saccharomyces cerevisiae) with normal and elevated levels of Cse4

2013-01-18 | E-GEOD-31466 | biostudies-arrayexpress

Tripartite organization of centromeric chromatin in budding yeast

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. We used micrococcal nuclease mapping, chromatin immunoprecipitation and paired-end sequencing to determine the structure of yeast centromeres at single base-pair resolution.

2011-12-07 | E-GEOD-28298 | biostudies-arrayexpress

Psh1-mediated Proteolysis Prevents the Budding Yeast Centromeric Histone Variant from Mislocalizing to Promoter Nucleosomes [ChIP-Seq]

Project description:Precise localization of the histone H3 variant CENP-A(Cse4) to centromeres is essential for accurate chromosome segregation. In budding yeast, CENP-A(Cse4) is regulated by ubiquitin-mediated proteolysis to ensure its exclusive localization to the centromere. Overexpression of CENP-A(Cse4) is lethal when the CENP-A(Cse4) E3 ubiquitin ligase, Psh1, is deleted. To identify the genomic sites of CENP-A(Cse4) mislocalization in this condition, we investigated the genome-wide mislocalization pattern of CENP-A(Cse4) by ChIP-seq.

2016-03-08 | GSE69695 | GEO

Psh1-mediated Proteolysis Prevents the Budding Yeast Centromeric Histone Variant from Mislocalizing to Promoter Nucleosomes [RNA-seq]

Project description:Precise localization of the histone H3 variant CENP-A(Cse4) to centromeres is essential for accurate chromosome segregation. In budding yeast, CENP-A(Cse4) is regulated by ubiquitin-mediated proteolysis to ensure its exclusive localization to the centromere. Overexpression of CENP-A(Cse4) is lethal when the CENP-A(Cse4) E3 ubiquitin ligase, Psh1, is deleted. CENP-A(Cse4) mislocalizes to promoters in this condition, so we investigated if there was an effect on gene expression of downstream genes using RNA-seq.

2016-03-08 | GSE77596 | GEO

RNA Seq analysis of WT haploid and Disome 10 in Saccharomyces cerevisiae

Project description:Aneuploidy and epigenetic alterations have long been associated with carcinogenesis, but it was unknown whether aneuploidy could disrupt the epigenetic states required for cellular differentiation. In this study, we found that ~3% of random aneuploid karyotypes in yeast disrupt the stable inheritance of silenced chromatin during cell proliferation. Karyotype analysis revealed that this phenotype was significantly correlated with gains of chromosomes III and X. Chromosome X disomy alone was sufficient to disrupt chromatin silencing and yeast mating-type identity as indicated by a lack of growth response to pheromone. The silencing defect was not limited to the cryptic mating type loci but was associated with global changes in histone modifications and chromatin localization of Sir2 histone deacetylase. The chromatin-silencing defect of disome X can be partially recapitulated by increasing the copy number of several genes on chromosome X. These results suggest that aneuploidy can directly cause epigenetic instability and disrupt cellular differentiation.

2017-09-12 | GSE98435 | GEO

ChIP Seq analysis of H3K4me3 and H3K79me3 in euploid and aneuploid Saccharomyces cerevisiae

2017-09-12 | GSE98282 | GEO

Analysis of gene expression by RNA Seq in mutants of Psh1, Cac2, or the double mutant relative to WT upon overexpression of Cse4 in Saccharomyces cerevisiae.

Project description:Correct localization of the centromeric histone variant CenH3/CENP-A/Cse4 is an important part of faithful chromosome segregation. Mislocalization of CenH3 could lead to ectopic centromere formation and missegregation, and could affect DNA replication and transcription. CENP-A is often overexpressed and mislocalized in cancer genomes, but the underlying mechanisms are not understood. One major regulator of Cse4 deposition is Psh1, an E3 ubiquitin ligase that controls levels of Cse4 to prevent deposition into noncentromeric regions. We present evidence that Chromatin assembly factor-1 (CAF-1), an evolutionarily conserved histone H3/H4 chaperone shown previously to interact with CenH3 in flies and human cells, regulates Cse4 deposition in budding yeast. Yeast CAF-1 (yCAF-1) is a heterotrimeric protein complex consisting of CAC1, CAC2, and CAC3, which interacts with Cse4, and can assemble Cse4 nucleosomes in vitro. yCAF-1 regulates the stability of both soluble and chromatin associated Cse4. Loss of yCAF-1 can rescue growth defects and changes in gene expression associated with Cse4 deposition that occur in the absence of Psh1-mediated proteolysis. Incorporation of Cse4 into promoter nucleosomes at transcriptionally active genes depends on yCAF-1. Overall our findings suggest CAF-1 can act as a CenH3 chaperone, regulating levels and incorporation of CenH3 in chromatin. Furthermore, the misincorporation of CenH3 at promoter regions may have negative consequences for gene expression.

2017-09-01 | GSE98396 | GEO

ChIP Seq analysis of Cse4 in mutants of Psh1, Cac2, the double mutant, and WT upon overexpression of Cse4 in Saccharomyces cerevisiae.

2017-09-01 | GSE98395 | GEO

Tripartite organization of centromeric chromatin in budding yeast

2011-12-07 | GSE28298 | GEO