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RDNA Array Length is a Major Determinant of Replicative Lifespan in Budding Yeast - RNAseq

ABSTRACT: In this study we perform RNA-seq of budding yeast strains with variable copy number of the rRNA genes (rDNA CN) to assess the relationship between rDNA CN and gene expression. RNA-seq was performed on samples both with and without polyA selection (for all transcripts and for rRNA transcripts, respectively).

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE193599 | GEO | 2022/04/05

REPOSITORIES: GEO

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rDNA Array Length is a Major Determinant of Replicative Lifespan in Budding Yeast - ATACseq

Project description:In this study we perform ATAC-seq of budding yeast strains with variable copy number of the rRNA genes (rDNA CN). We aim to better understand the relationship between DNA accessibility and replicative lifespan in strains with variable rDNA CN.

2022-04-05 | GSE193598 | GEO

rDNA array length is a major determinant of replicative lifespan in budding yeast.

Project description:The complex processes and interactions that regulate aging and determine lifespan are not fully defined for any organism. Here, taking advantage of recent technological advances in studying aging in budding yeast, we discovered a previously unappreciated relationship between the number of copies of the ribosomal RNA gene present in its chromosomal array and replicative lifespan (RLS). Specifically, the chromosomal ribosomal DNA (rDNA) copy number (rDNA CN) positively correlated with RLS and this interaction explained over 70% of variability in RLS among a series of wild-type strains. In strains with low rDNA CN, SIR2 expression was attenuated and extrachromosomal rDNA circle (ERC) accumulation was increased, leading to shorter lifespan. Suppressing ERC formation by deletion of FOB1 eliminated the relationship between rDNA CN and RLS. These data suggest that previously identified rDNA CN regulatory mechanisms limit lifespan. Importantly, the RLSs of reported lifespan-enhancing mutations were significantly impacted by rDNA CN, suggesting that changes in rDNA CN might explain the magnitude of some of those reported effects. We propose that because rDNA CN is modulated by environmental, genetic, and stochastic factors, considering rDNA CN is a prerequisite for accurate interpretation of lifespan data.

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rDNA Array Length is a Major Determinant of Replicative Lifespan in Budding Yeast.

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-04-05 | GSE193600 | GEO

rDNA Array Length is a Major Determinant of Replicative Lifespan in Budding Yeast.

Project description:rDNA Array Length is a Major Determinant of Replicative Lifespan in Budding Yeast.

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rDNA Array Length is a Major Determinant of Replicative Lifespan in Budding Yeast - RNAseq

Project description:rDNA Array Length is a Major Determinant of Replicative Lifespan in Budding Yeast - RNAseq

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rDNA Array Length is a Major Determinant of Replicative Lifespan in Budding Yeast - ATACseq

Project description:rDNA Array Length is a Major Determinant of Replicative Lifespan in Budding Yeast - ATACseq

| PRJNA796838 | ENA

Insulin signaling regulates R2 retrotransposon expression to orchestrate transgenerational rDNA copy number maintenance

Project description:Preserving a large number of essential yet highly unstable ribosomal DNA (rDNA) repeats is critical for the germline to perpetuate the genome through generations. Spontaneous rDNA loss must be countered by rDNA copy number (CN) expansion. Germline rDNA CN expansion is best understood in Drosophila melanogaster, which relies on unequal sister chromatid exchange (USCE) initiated by DNA breaks at rDNA. The rDNA-specific retrotransposon R2 responsible for USCE-inducing DNA breaks is typically expressed only when rDNA CN is low to minimize the danger of DNA breaks; however, the underlying mechanism of R2 regulation remains unclear. Here we identify the insulin receptor (InR) as a major repressor of R2 expression, limiting unnecessary R2 activity. Through single-cell RNA sequencing we find that male germline stem cells (GSCs), the major cell type that undergoes rDNA CN expansion, have reduced InR expression when rDNA CN is low. Reduced InR activity in turn leads to R2 expression and CN expansion. We further find that dietary manipulation alters R2 expression and rDNA CN expansion activity. This work reveals that the insulin pathway integrates rDNA CN surveying with environmental sensing, revealing a potential mechanism by which diet exerts heritable changes to genomic content.

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Repression of damaged and intact rDNA by the SUMO pathway

Project description:Ribosomal RNAs (rRNAs) are essential components of the ribosome and are among the most abundant macromolecules in the cell. To ensure high rRNA level, eukaryotic genomes contain dozens to hundreds of rDNA genes, however, only a fraction of the rRNA genes seems to be active, while others are transcriptionally silent. In Drosophila rDNA units damaged by insertions of retrotransposons are repressed by an unknown mechanism. Here, we established a new model to study regulation of rDNA expression using molecularly marked rDNA transgenes. Using this model, we show that insertion of any heterologous sequence into rDNA leads to transcriptional repression. We found that SUMO (Small Ubiquitin-like Modifier) is required for efficient repression of damaged rDNA units. Surprisingly, SUMO also controls expression of intact rDNA, demonstrating that a single pathway is responsible for both selective repression of damaged units and silencing of surplus rDNA.

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Project description:As the molecular mechanisms of biological aging become better understood, there is growing interest in identifying interventions that target those mechanisms to promote extended health and longevity. The budding yeast Saccharomyces cerevisiae has served as a premier model organism for identifying genetic and molecular factors that modulate cellular aging and is a powerful system in which to evaluate candidate longevity interventions. Here we screened a collection of natural products and natural product mixtures for effects on the growth rate, mTOR-mediated growth inhibition, and replicative lifespan. No mTOR inhibitory activity was detected, but several of the treatments affected growth rate and lifespan. The strongest lifespan shortening effects were observed for green tea extract and berberine. The most robust lifespan extension was detected from an extract of Pterocarpus marsupium and another mixture containing Pterocarpus marsupium extract. These findings illustrate the utility of the yeast system for longevity intervention discovery and identify Pterocarpus marsupium extract as a potentially fruitful longevity intervention for testing in higher eukaryotes.

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DDX18 safeguards rDNA epigenetic landscape by counteracting PRC2 and maintains ESC identity

Project description:Here we have RNA binding protein DDX18 connecting rRNA transcription to early embryo development and embryonic stem cell (ESC) identity maintenance. DDX18 mutant embryos suffer lethality during preimplantation development. DDX18 depletion impairs ESC self-renewal and pluripotency, which phenotype-copies RNA polymerase I (RNAPI) inhibition. Mechanistically, DDX18 is recruited to rDNA by RNAPI transcription machinery and senses rRNA transcription by binding to pre-rRNA. In nucleolus, DDX18 surrounds DFC ring and interacts with PRC2. In the presence of transcribed pre-rRNA, DDX18 interaction with PRC2 makes EZH2 unstably binding to the other components of PRC2, thereby preventing PRC2 engagement and counteracting H3K27me3 mediated silencing at rDNA chromatin. Together, our study shows that DDX18 plays important roles in safeguarding ESCs identity through regulating epigenetic states of rDNA locus and maintaining euchromatin structure in nucleolus.

2019-12-25 | GSE124580 | GEO

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