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H3K36 methylation promotes longevity by enhancing transcriptional fidelity [Yeast RNA-Seq]

ABSTRACT: Epigenetic mechanisms including histone post-translational modifications control longevity in diverse organisms. Relatedly, loss of proper transcriptional regulation on a global scale is an emerging aspect of shortened lifespan, but the specific mechanisms linking these observations remain to be uncovered. Here, we describe a lifespan screen in S. cerevisiae, designed to identify altered amino acid residues of histones that alter yeast replicative aging. Our results reveal that lack of sustained H3K36 methylation is commensurate with increased cryptic transcription in a set of genes in old cells and shorter lifespan. Deletion of the K36me2/3 demethylase Rph1 increases H3K36me3 within these genes and suppresses cryptic transcript initiation to extend lifespan. We show that this aging phenomenon is conserved, as cryptic transcription also increases in old worms. We propose that epigenetic misregulation in aging cells leads to an increase in transcriptional noise that is detrimental to lifespan, and, importantly, this acceleration in aging can be reversed by restoring transcriptional fidelity.

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE65764 | GEO | 2015/07/17

SECONDARY ACCESSION(S): PRJNA274977

REPOSITORIES: GEO

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H3K36 methylation promotes longevity by enhancing transcriptional fidelity [ChIP-Seq]

Project description:Epigenetic mechanisms including histone post-translational modifications control longevity in diverse organisms. Relatedly, loss of proper transcriptional regulation on a global scale is an emerging aspect of shortened lifespan, but the specific mechanisms linking these observations remain to be uncovered. Here, we describe a lifespan screen in S. cerevisiae, designed to identify altered amino acid residues of histones that alter yeast replicative aging. Our results reveal that lack of sustained H3K36 methylation is commensurate with increased cryptic transcription in a set of genes in old cells and shorter lifespan. Deletion of the K36me2/3 demethylase Rph1 increases H3K36me3 within these genes and suppresses cryptic transcript initiation to extend lifespan. We show that this aging phenomenon is conserved, as cryptic transcription also increases in old worms. We propose that epigenetic misregulation in aging cells leads to an increase in transcriptional noise that is detrimental to lifespan, and, importantly, this acceleration in aging can be reversed by restoring transcriptional fidelity.

2015-07-17 | GSE65766 | GEO

H3K36 methylation promotes longevity by enhancing transcriptional fidelity [Worm RNA-Seq]

2015-07-17 | GSE65765 | GEO

Histone Demethylase UTX-1 Regulates the Caenorhabditis elegans Lifespan by Targeting the Insulin/IGF-1 Signaling Pathway

Project description:Epigenetic modifications are thought to be important for gene expression changes during development and aging. However, besides the Sir2 histone deacetylase in somatic tissues and H3K4 trimethylation in germlines, there is scant evidence implicating epigenetic regulations in aging. The insulin/IGF-1 signaling (IIS) pathway is a major lifespan regulatory pathway. Here we show that progressive increases in gene expression and loss of H3K27me3 on IIS components are due, at least in part, to increased activity of the H3K27 demethylase UTX-1 during aging. RNAi of the utx-1 gene extended the mean lifespan of C. elegans by ~30%, dependent on DAF-16 activity and not additive in daf-2 mutants. The loss of utx-1 increased H3K27me3 on the Igf1r/daf-2 gene and decreased IIS activity leading to a more "naive" epigenetic state. Like stem cell reprogramming, our results suggest that reestablishing epigenetic marks lost during aging might help "reset" the developmental age of animal cells. Examination of H3K27me3 in young and old worms without or with Utx-1 RNAi.

2011-11-22 | E-GEOD-29896 | biostudies-arrayexpress

Transcriptional response to MnSOD over-expression in Drosophila melanogaster

Project description:Profiled the transcriptional response to over-expression Manganese-SOD (MnSOD) in adult Drosophila. A doxycycline-regulated system was employed to induce MnSOD over-expression, resulting in mean and maximal lifespan increases of ~ 20%. Examination of the genome-wide response to this lifespan intervention provided key insights into the molecular basis of aging. Keywords: genetic modification; MnSOD over-expression

2008-01-01 | GSE7159 | GEO

Expression data from wild-type and rph1-deleted yeasts

Project description:Cells respond to environmental signals by alteration of gene expression through action of transcription factors. A JmjC-domain-containing protein Rph1 belongs to the C2H2 zinc finger protein family and functions to repress transcription of PHR1 via histone demethylation. However, additional targets of Rph1 remain largely unknown. Here, we investigate the regulatory network of Rph1 by microarray analyses. More than 75% of Rph1-regulated genes showed increased expression in rph1M-NM-^T, suggesting Rph1 serves as a transcriptional repressor under physiological conditions. The binding motif of Rph1 resembling the STress Response Element (STRE) was over-represented in the promoters of Rph1-repressed genes. In addition, significant proportions of Rph1-regulated genes responded to DNA damage and environmental stress, implying a repressive role of Rph1 in the cross-protection of stress responses. We used expression microarray to identify Rph1-regulated genes and established Rph1 functioned as a transcriptional repressor to link DNA damage signaling and general stress response. We compared gene expression in wild-type and rph1-deleted strains cultured in rich medium (YPD) during exponential growth. 3 biological samples were analyzed.

2013-11-06 | E-GEOD-39950 | biostudies-arrayexpress

A metabolic switch at the center of JNK-induced proteostasis and longevity

Project description:Aging is associated with a progressive loss of tissue and metabolic homeostasis. Changes in the cellular management of the proteome, as well as changes in cellular metabolism have been implicated in this decline, yet our understanding of causal relationships between these changes remains incomplete. Genetic studies have shown that single-gene perturbations are sufficient to significantly impact the aging process, delaying all associated cellular deficiencies, and thus increasing lifespan. Here, we explore metabolic and proteostatic changes associated with lifespan extension by one such perturbation. Focusing on the Drosophila brain, we comprehensively characterize protein turnover rates and assess metabolic flux to identify changes in protein and metabolic homeostasis in long-lived animals. Using organism-wide 15N labeling, we observe that the turnover rates of ~2000 proteins in the fly head decline with age, and that this decline is prevented in animals with lifespan-extending elevation of Jun-N-terminal Kinase (JNK) activity. Combining transcriptomic, metabolomic, and metabolic flux analysis, we find that JNK activation in the brain results in decreased steady-state Glucose-6-phosphate levels coupled to elevated carbon flux into the pentose phosphate pathway due to the transcriptional induction of Glucose-6-phosphate Dehydrogenase. This metabolic change promotes proteostasis in the aging brain, likely via increased NADPH against oxidative stress response. Through a comprehensive characterization of the cellular and biochemical changes elicited by a lifespan extending mutation, our study thus identifies a JNK-induced metabolic switch that increases lifespan by promoting neuronal proteostasis.

| MSV000080118 | MassIVE

One-day thermal regime extends lifespan

Project description:Environmental factors such as temperature can modulate animal’s lifespan. However, the underlying mechanisms remain largely undefined. Through proteomic analysis of C. elegans at different time points (young adult, middle age, and old age) and under two temperature conditions (20°C and 25°C), we found that temperature affects C. elegans lifespan largely by modulating the proteostasis. Surprisingly, although animals live shorter at the higher temperature, we found that worms cultured at 25°C for one day at early adulthood promotes the protein homeostasis by decreasing the synthesis and increasing the degradation, suggesting the beneficial effects. Consistent with the finding, animals shifting from 20°C to 25°C for 24 hours between the larval L4 to adult Day 3 stages indeed live longer and are more resistant to stresses. Furthermore, we found that the one-day thermal induced lifespan extension is mediated by the FOXO transcriptional factor DAF-16. These results reveal an unexpected and complicated mechanism underlying the temperature effects on aging, which could potentially aid to develop strategies for treating aging related diseases.

2023-03-11 | PXD024916 | Pride

Expression data from wild-type and rph1-deleted yeasts

Project description:Cells respond to environmental signals by alteration of gene expression through action of transcription factors. A JmjC-domain-containing protein Rph1 belongs to the C2H2 zinc finger protein family and functions to repress transcription of PHR1 via histone demethylation. However, additional targets of Rph1 remain largely unknown. Here, we investigate the regulatory network of Rph1 by microarray analyses. More than 75% of Rph1-regulated genes showed increased expression in rph1Δ, suggesting Rph1 serves as a transcriptional repressor under physiological conditions. The binding motif of Rph1 resembling the STress Response Element (STRE) was over-represented in the promoters of Rph1-repressed genes. In addition, significant proportions of Rph1-regulated genes responded to DNA damage and environmental stress, implying a repressive role of Rph1 in the cross-protection of stress responses.

2013-11-06 | GSE39950 | GEO

Ssd1 and Gcn2 suppress global translational efficiency in replicatively aged yeast, while their activation in young cells extends lifespan

Project description:Using ribosome profiling, we find globally reduced translation efficiency during mitotic / replicative aging in budding yeast. Two mechanisms contribute to this: Firstly, the mRNA binding protein Ssd1 is induced during aging, sequestering mRNAs to P-bodies and stress granules that are abundant in old cells. Indeed, overexpression of Ssd1 reduced protein synthesis in young cells and extended lifespan, while loss of Ssd1 reduced the translational deficit of old cells and shortened lifespan. Secondly, the Gcn2 kinase is activated in old cells, phosphorylating and inactivating the translational initiation factor eIF2α. Accordingly, deletion of GCN2 reduced the translational defect of old cells. Furthermore, overexpressing an uncharged tRNA to fully activate Gcn2, or overexpression of its downstream mediator, Gcn4, extended replicative lifespan in a manner that was mostly dependent on autophagy without inhibiting the TOR pathway. As such, Ssd1 induction, activation of the integrated stress response or autophagy are favorable TOR-independent therapeutic targets for lifespan extension.

2018-08-10 | GSE104506 | GEO

Restoration of energy homeostasis by SIRT6 extends healthy lifespan

Project description:Aging leads to a gradual decline in physical activity and disrupted energy homeostasis. The NAD+-dependent SIRT6 deacylase regulates aging and metabolism through mechanisms that largely remain unknown. Here, we show that SIRT6 overexpression leads to a reduction in frailty and lifespan extension in both male and female B6 mice. A combination of physiological assays, in vivo multi-omics analyses and 13C lactate tracing identified an age-dependent decline in glucose homeostasis and hepatic gluconeogenesis (GNG) capacity in wild type mice. In contrast, aged SIRT6-transgenic mice preserve GNG capacity and glucose homeostasis through an improvement in the utilization of two major GNG precursors, lactate and glycerol. To mediate these changes, mechanistically, SIRT6 increases hepatic GNG gene expression, de novo NAD+ synthesis, and systemically enhances glycerol release from adipose tissue. These findings show that SIRT6 optimizes energy homeostasis in old age to delay frailty and preserve healthy aging.

2021-03-11 | PXD021447 | Pride

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