The Nuts and Bolts of Transcriptionally Silent Chromatin in <i>Saccharomyces cerevisiae</i>

Gartenberg, Marc R.; Smith, Jeffrey S.

doi:10.1534/genetics.112.145243

Cited by 136 publications

(171 citation statements)

References 425 publications

(604 reference statements)

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“…Strikingly, we found that the disruption of SIR2 did not significantly increase global levels of H4K16ac in either NDT80 or ndt80 cells (Figures 5 and 6C), consistent with the notion that Sir2 is not the main genome-wide H4K16ac deacetylase and its action may be specifically restricted to precise heterochromatic domains 5354. On the other hand, SAS2 deletion clearly, but not completely, reduced H4K16ac (Figures 5 and 6C), suggesting that Sas2 is the main, but not the only, H4K16 acetyltransferase acting in the meiotic cell cycle.…”

Section: Resultssupporting

confidence: 85%

Impact of histone H4K16 acetylation on the meiotic recombination checkpoint in Saccharomyces cerevisiae

Cavero¹,

Herruzo

Ontoso³

et al. 2016

Microb Cell

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In meiotic cells, the pachytene checkpoint or meiotic recombination checkpoint is a surveillance mechanism that monitors critical processes, such as recombination and chromosome synapsis, which are essential for proper distribution of chromosomes to the meiotic progeny. Failures in these processes lead to the formation of aneuploid gametes. Meiotic recombination occurs in the context of chromatin; in fact, the histone methyltransferase Dot1 and the histone deacetylase Sir2 are known regulators of the pachytene checkpoint in Saccharomyces cerevisiae. We report here that Sas2-mediated acetylation of histone H4 at lysine 16 (H4K16ac), one of the Sir2 targets, modulates meiotic checkpoint activity in response to synaptonemal complex defects. We show that, like sir2, the H4-K16Q mutation, mimicking constitutive acetylation of H4K16, eliminates the delay in meiotic cell cycle progression imposed by the checkpoint in the synapsis-defective zip1 mutant. We also demonstrate that, like in dot1, zip1-induced phosphorylation of the Hop1 checkpoint adaptor at threonine 318 and the ensuing Mek1 activation are impaired in H4-K16 mutants. However, in contrast to sir2 and dot1, the H4-K16R and H4-K16Q mutations have only a minor effect in checkpoint activation and localization of the nucleolar Pch2 checkpoint factor in ndt80-prophase-arrested cells. We also provide evidence for a cross-talk between Dot1-dependent H3K79 methylation and H4K16ac and show that Sir2 excludes H4K16ac from the rDNA region on meiotic chromosomes. Our results reveal that proper levels of H4K16ac orchestrate this meiotic quality control mechanism and that Sir2 impinges on additional targets to fully activate the checkpoint.

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Section: Resultssupporting

confidence: 85%

Impact of histone H4K16 acetylation on the meiotic recombination checkpoint in Saccharomyces cerevisiae

Cavero¹,

Herruzo

Ontoso³

et al. 2016

Microb Cell

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“…Previous studies showed that the aging phenotype with small round daughters could be related to an age-dependent mitochondrial dysfunction (9,12), but the molecular mechanisms underlying the other aging type characterized by elongated daughters remain largely unclear. Our results revealed that the sustained rDNA silencing loss, which can lead to genome instability (18), is specifically associated with the aging phenotype featured by elongated daughters. In support of this, young mother cells can also sporadically produce a few elongated daughters, the occurrence of which correlates with the transient silencing loss during the early phases of their life spans (Fig.…”

Section: Significancementioning

confidence: 69%

“…A major contributor to the maintenance of genome stability is chromatin silencing, which causes a locally inaccessible heterochromatin structure that represses transcription, recombination, and DNA damage. The heterochromatic regions in yeast include the silent mating-type (HM) loci, rDNA, and subtelomeric regions (18). Among them, the rDNA region on chromosome XII consists of 100∼200 tandem repeats and is a particularly fragile genomic site, the stability of which closely connects to the RLS (19)(20)(21).…”

Section: Resultsmentioning

confidence: 99%

“…We observed that cells with the rDNA reporter gene exhibit weak fluorescence; in contrast, cells carrying the same reporter at the URA3 locus, which is not subject to silencing, show very high fluorescence. In addition, deletion of SIR2, which is required for rDNA silencing (18), yields significantly increased reporter expression at the rDNA, but not at URA3 (SI Appendix, Fig. S1E).…”

Section: Significancementioning

confidence: 99%

“…Chromatin silencing at the rDNA is primarily mediated by the lysine deacetylase Sir2, encoded by the best-studied longevity gene to date, which is conserved from bacteria to humans (18). To examine the role of Sir2 in regulating silencing dynamics, we monitored the aging process of sir2Δ cells.…”

Section: Significancementioning

confidence: 99%

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Multigenerational silencing dynamics control cell aging

Jin

O’Laughlin

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

103

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Cellular aging plays an important role in many diseases, such as cancers, metabolic syndromes, and neurodegenerative disorders. There has been steady progress in identifying aging-related factors such as reactive oxygen species and genomic instability, yet an emerging challenge is to reconcile the contributions of these factors with the fact that genetically identical cells can age at significantly different rates. Such complexity requires single-cell analyses designed to unravel the interplay of aging dynamics and cell-to-cell variability. Here we use microfluidic technologies to track the replicative aging of single yeast cells and reveal that the temporal patterns of heterochromatin silencing loss regulate cellular life span. We found that cells show sporadic waves of silencing loss in the heterochromatic ribosomal DNA during the early phases of aging, followed by sustained loss of silencing preceding cell death. Isogenic cells have different lengths of the early intermittent silencing phase that largely determine their final life spans. Combining computational modeling and experimental approaches, we found that the intermittent silencing dynamics is important for longevity and is dependent on the conserved Sir2 deacetylase, whereas either sustained silencing or sustained loss of silencing shortens life span. These findings reveal that the temporal patterns of a key molecular process can directly influence cellular aging, and thus could provide guidance for the design of temporally controlled strategies to extend life span.replicative aging | single-cell analysis | microfluidics | chromatin silencing | computational modeling C ellular aging is generally driven by the accumulation of genetic and cellular damage (1, 2). Although much progress has been made in identifying molecular factors that influence life span, what remains sorely missing is an understanding of how these factors interact and change dynamically during the aging process. This is in part because aging is a complex process wherein isogenic cells have various intrinsic causes of aging and widely different rates of aging. As a result, static population-based approaches could be insufficient to fully reveal sophisticated dynamic changes during aging. Recent developments in single-cell analyses to unravel the interplay of cellular dynamics and variability hold the promise to answer that challenge (3-5). Here we chose the replicative aging of yeast S. cerevisiae as a model and exploited quantitative biology technologies to study the dynamics of molecular processes that control aging at the single-cell level.

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