A new experimental platform facilitates assessment of the transcriptional and chromatin landscapes of aging yeast

Hendrickson, David G.; Soifer, Ilya; Wranik, Bernd J.; Kim, Griffin; Robles, Michael; Gibney, Patrick A.; McIsaac, R. Scott

doi:10.7554/elife.39911

Cited by 62 publications

(111 citation statements)

References 80 publications

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“…Using gene ontology enrichment analysis for biological processes [54], we identify SRP-dependent protein localization and protein translocation to the ER as commonly downregulated across cell identities. This observation is consistent with the observed interaction of protein translocation systems with aging [40, 87] (Fig. 3C, lower).…”

Section: Resultssupporting

confidence: 92%

“…This core is characterized by decreased expression of genes involved in SRP-dependent protein translation and protein targeting to the ER and increased expression of genes involved in inflammation. Decreased protein translation and targeting to the ER has previously been associated with replicative age in S. cerevisiea [40] and is consistent with associations between global protein translation and aging [87]. Likewise, increased inflammatory pathway expression has been broadly observed in studies of aging tissues [12, 70, 78, 3].…”

Section: Discussionsupporting

confidence: 58%

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A murine aging cell atlas reveals cell identity and tissue-specific trajectories of aging

Kimmel

Penland

Rubinstein

et al. 2019

Preprint

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Background: Aging is a pleiotropic process affecting many aspects of organismal and cellular 1 physiology. Mammalian organisms are composed of a constellation of distinct cell type and state 2 identities residing within different tissue environments. Due to technological limitations, the study 3 of aging has traditionally focused on changes within individual cell types, or the aggregate changes 4 across cell types within a tissue. The influence of cell identity and tissue environment on the trajectory 5 of aging therefore remains unclear.6Results: Here, we perform single cell RNA-seq on >50,000 individual cells across three tissues in 7 young and aged mice. These molecular profiles allow for comparison of aging phenotypes across cell 8 types and tissue environments. We find transcriptional features of aging common across many cell 9 types, as well as features of aging unique to each type. Leveraging matrix factorization and optimal 10 transport methods, we compute a trajectory and magnitude of aging for each cell type. We find that 11 cell type exerts a larger influence on these measures than tissue environment. 12Conclusion: In this study, we use single cell RNA-seq to dissect the influence of cell identity and 13 tissue environment on the aging process. Single cell analysis reveals that cell identities age in unique 14 ways, with some common features of aging shared across identities. We find that both cell identities 15 and tissue environments exert influence on the trajectory and magnitude of aging, with cell identity 16 influence predominating. These results suggest that aging manifests with unique directionality and 17 magnitude across the diverse cell identities in mammals. 18 Introduction 19Aging is a gradual process of functional and homeostatic decline in living systems. This decline results in increased 20 mortality risk and disease prevalence, eventually resulting in death. Aging appears to be a conserved feature of 21 eukaryotic biology, affecting organisms as phylogenetically diverse as the single celled S. cerevisiea, the eutelic 22 nematode C. elegans, mice, and humans [45, 63, 91]. Despite the near universal nature of the aging process, the 23 underlying causes of aging are poorly understood. Aging phenotypes have been observed and hypotheses have been 24 proposed for more than a hundred years [97, 50, 37, 64], but we do not yet know the cellular and molecular players 25 that cause aging or how they differ between biological contexts. Both the fundamental nature of aging and its negative 26 effects provide motivation to enumerate these players and establish causal relationships among aging phenotypes. 27Mammalian aging phenotypes manifest at the organismal, tissue, cellular, and molecular levels [100]. Extensive 28 research has produced catalogs of aging phenotypes at the physiological level, providing functional and behavioral 29 * Equal Contribution † Current Address: DuPont Nutrition and Biosciences, 200 Powder Mill Rd, Wilmington, DE, 19803 PREPRINT hallmarks of age related decline. Likewi...

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Section: Resultssupporting

confidence: 92%

Section: Discussionsupporting

confidence: 58%

A murine aging cell atlas reveals cell identity and tissue-specific trajectories of aging

Kimmel

Penland

Rubinstein

et al. 2019

Preprint

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“…In order to correct for this problem, the authors added propidium monoazide which can only enter dead cells and binds to DNA preventing inclusion of dead cells in the ATAC‐seq data. Using this approach, shifts in nucleosome occupancy with age were detected, but not the dramatic reduction in total occupancy, as has been previously reported …”

Section: Population‐level Systems Biology Approaches To Understandingsupporting

confidence: 80%

“…Recently, a miniature‐chemostat method has been described that relied on similar principles to enable larger, parallelized experiments . To accomplish this, they modified miniature‐chemostat to incorporate magnets to hold biotinylated mother cells in place while flowing over fresh media and removing daughter cells.…”

Section: Population‐level Systems Biology Approaches To Understandingmentioning

confidence: 99%

Trajectories of Aging: How Systems Biology in Yeast Can Illuminate Mechanisms of Personalized Aging

et al. 2019

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All organisms age, but the extent to which all organisms age the same way remains a fundamental unanswered question in biology. Across species, it is now clear that at least some aspects of aging are highly conserved and are perhaps universal, but other mechanisms of aging are private to individual species or sets of closely related species. Within the same species, however, it has generally been assumed that the molecular mechanisms of aging are largely invariant from one individual to the next. With the development of new tools for studying aging at the individual cell level in budding yeast, recent data has called this assumption into question. There is emerging evidence that individual yeast mother cells may undergo fundamentally different trajectories of aging. Individual trajectories of aging are difficult to study by traditional population level assays, but through the application of systems biology approaches combined with novel microfluidic technologies, it is now possible to observe and study these phenomena in real time. Understanding the spectrum of mechanisms that determine how different individuals age is a necessary step toward the goal of personalized geroscience, where healthy longevity is optimized for each individual.

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“…A prominent feature of somatic aging is the breakdown of heterochromatic domains and expression of transposable elements (TEs), which are typically repressed (López-Otín et al 2013;Cecco et al 2013;Benayoun et al 2018;Jones et al 2016;Li et al 2013;Patterson et al 2015;Hendrickson et al 2018;Sousa-Victor et al 2017). Although TE expression is likely a secondary effect of heterochromatin disruption, mounting evidence suggests that suppressing TE mobilization can extend lifespan Jones et al 2016;Wang et al 2011;Cecco et al 2019;Simon et al 2019).…”

Section: Introductionmentioning

confidence: 99%

PIWI-piRNA pathway-mediated transposable element repression inHydrasomatic stem cells

Teefy

Siebert

Cazet

et al. 2019

Preprint

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Transposable elements (TEs) can damage genomes, thus organisms employ a variety of mechanisms to repress TE expression. However, these mechanisms often fail over time leading to de-repression of TEs in aging tissues. The PIWI-piRNA pathway is a small RNA pathway that represses TE expression in the germline of animals. Here we explore the function of the pathway in the epithelial stem cells of Hydra, a long-lived freshwater cnidarian. Hydra have three stem cell populations; endodermal and ectodermal epithelial stem cells are strictly somatic, whereas the interstitial stem cells retain germline competence. In our previous study, we found that the PIWI proteins are expressed in all three Hydra stem cell types. In this study, we focus on the ectodermal and endodermal epithelial stem cells to understand the somatic function of the pathway. We isolated piRNAs from Hydra that lack the interstitial lineage and found that these somatic piRNAs map predominantly to TE transcripts and display the conserved sequence signatures typical of germline piRNAs. Three lines of evidence suggest that the PIWI-piRNA pathway represses TEs in Hydra epithelial stem cells. First, epithelial knockdown of the Hydra PIWI protein hywi resulted in upregulation of TE expression. Second, degradome sequencing revealed evidence of PIWImediated cleavage of TE RNAs in epithelial cells using the ping-pong mechanism. Finally, we demonstrated a direct association between Hywi protein and TE transcripts in epithelial cells using RNA immunoprecipitation. Interestingly, we found that RNAi knockdown of hywi leads to an upregulation of genes involved in innate immunity, which may be in response to TE upregulation; this is consistent with recent studies on TE expression in mammalian cells. Altogether, this study suggests a function for the PIWI-piRNA pathway in maintaining the long-lived somatic cell lineages of Hydra and may point to a broader role for this pathway in protecting somatic tissue from TE-induced damage.

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A new experimental platform facilitates assessment of the transcriptional and chromatin landscapes of aging yeast

Cited by 62 publications

References 80 publications

A murine aging cell atlas reveals cell identity and tissue-specific trajectories of aging

A murine aging cell atlas reveals cell identity and tissue-specific trajectories of aging

Trajectories of Aging: How Systems Biology in Yeast Can Illuminate Mechanisms of Personalized Aging

PIWI-piRNA pathway-mediated transposable element repression inHydrasomatic stem cells

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