Identification of High-Copy Disruptors of Telomeric Silencing in Saccharomyces cerevisiae

Singer, M; Kahana, Alon; Wolf, Alexander J.; Meisinger, Lia L.; Peterson, Suzanne E.; Goggin, Colin; Mahowald, Maureen; Gottschling, Daniel E.

doi:10.1093/genetics/150.2.613

Cited by 414 publications

(35 citation statements)

References 89 publications

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“…For example, finding mutations which enhance the probability of spontaneous nucleation would be of great interest. The study on disruptors of telomeric silencing has possibly already unearthed some of these mutants [28] in S. cerevisiae. However, there could be much more to the mechanism of control of silencing.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic chromatin silencing: bistability and front propagation

Sedighi

Sengupta

2007

Phys. Biol.

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The role of post-translational modification of histones in eukaryotic gene regulation is well recognized. Epigenetic silencing of genes via heritable chromatin modifications plays a major role in cell fate specification in higher organisms. We formulate a coarse-grained model of chromatin silencing in yeast and study the conditions under which the system becomes bistable, allowing for different epigenetic states. We also study the dynamics of the boundary between the two locally stable states of chromatin: silenced and unsilenced. The model could be of use in guiding the discussion on chromatin silencing in general. In the context of silencing in budding yeast, it helps us understand the phenotype of various mutants, some of which may be non-trivial to see without the help of a mathematical model. One such example is a mutation that reduces the rate of background acetylation of particular histone side chains that competes with the deacetylation by Sir2p. The resulting negative feedback due to a Sir protein depletion effect gives rise to interesting counterintuitive consequences. Our mathematical analysis brings forth the different dynamical behaviors possible within the same molecular model and guides the formulation of more refined hypotheses that could be addressed experimentally.

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Section: Discussionmentioning

confidence: 99%

Epigenetic chromatin silencing: bistability and front propagation

Sedighi

Sengupta

2007

Phys. Biol.

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“…H3K79me2/3 can also maintain enhancerpromoter interactions at a subset of enhancers (Godfrey et al, 2019). H3K79 methylation has also been implicated in telomere silencing (Singer et al, 1998), recombination, DNA repair and cell cycle progression (Nguyen and Zhang, 2011). Monomethylation and trimethylation of H3K79 has been associated with gene activation and gene repression, respectively, in some studies (Barski et al, 2007).…”

Section: H3k79 Methylationmentioning

confidence: 99%

Is There a Histone Code for Cellular Quiescence?

Bonitto

Sarathy

Atai

et al. 2021

Front. Cell Dev. Biol.

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Many of the cells in our bodies are quiescent, that is, temporarily not dividing. Under certain physiological conditions such as during tissue repair and maintenance, quiescent cells receive the appropriate stimulus and are induced to enter the cell cycle. The ability of cells to successfully transition into and out of a quiescent state is crucial for many biological processes including wound healing, stem cell maintenance, and immunological responses. Across species and tissues, transcriptional, epigenetic, and chromosomal changes associated with the transition between proliferation and quiescence have been analyzed, and some consistent changes associated with quiescence have been identified. Histone modifications have been shown to play a role in chromatin packing and accessibility, nucleosome mobility, gene expression, and chromosome arrangement. In this review, we critically evaluate the role of different histone marks in these processes during quiescence entry and exit. We consider different model systems for quiescence, each of the most frequently monitored candidate histone marks, and the role of their writers, erasers and readers. We highlight data that support these marks contributing to the changes observed with quiescence. We specifically ask whether there is a quiescence histone “code,” a mechanism whereby the language encoded by specific combinations of histone marks is read and relayed downstream to modulate cell state and function. We conclude by highlighting emerging technologies that can be applied to gain greater insight into the role of a histone code for quiescence.

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“…Experiments largely rely on the behavior of knock-out mutants to unravel the components of the yeast silencing system. Less well-studied are the inhibition/enhancement (of enzymatic activity) or over/under-expression (of proteins), though overexpression of Sir proteins and Dot1 have been examined [23,44,54,60,62,64,79]. We argue that compared to knock-out mutants, inhibition etc.…”

Section: Introductionmentioning

confidence: 95%

“…Active sites in budding yeast chromatin are not only hyper-acetylated at particular histone tail sites but also tend to be hyper-methylated at certain key residues [49,54,55,79,89]. One of the DOT (Disruptor Of Telomeric Silencing) proteins, Dot1, methylates H3K79 residue and competes in binding with Sir3 for the same basic patch on the histone core region (H3K79) [2,46,74,89].…”

Section: Primer On Molecular Biology Of Budding Yeast Silencingmentioning

confidence: 99%

The Role of Multiple Marks in Epigenetic Silencing and the Emergence of a Stable Bivalent Chromatin State

Mukhopadhyay

Sengupta

2013

PLoS Comput Biol

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We introduce and analyze a minimal model of epigenetic silencing in budding yeast, built upon known biomolecular interactions in the system. Doing so, we identify the epigenetic marks essential for the bistability of epigenetic states. The model explicitly incorporates two key chromatin marks, namely H4K16 acetylation and H3K79 methylation, and explores whether the presence of multiple marks lead to a qualitatively different systems behavior. We find that having both modifications is important for the robustness of epigenetic silencing. Besides the silenced and transcriptionally active fate of chromatin, our model leads to a novel state with bivalent (i.e., both active and silencing) marks under certain perturbations (knock-out mutations, inhibition or enhancement of enzymatic activity). The bivalent state appears under several perturbations and is shown to result in patchy silencing. We also show that the titration effect, owing to a limited supply of silencing proteins, can result in counter-intuitive responses. The design principles of the silencing system is systematically investigated and disparate experimental observations are assessed within a single theoretical framework. Specifically, we discuss the behavior of Sir protein recruitment, spreading and stability of silenced regions in commonly-studied mutants (e.g., sas2 , dot1 ) illuminating the controversial role of Dot1 in the systems biology of yeast silencing.

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Identification of High-Copy Disruptors of Telomeric Silencing in Saccharomyces cerevisiae

Cited by 414 publications

References 89 publications

Epigenetic chromatin silencing: bistability and front propagation

Epigenetic chromatin silencing: bistability and front propagation

Is There a Histone Code for Cellular Quiescence?

The Role of Multiple Marks in Epigenetic Silencing and the Emergence of a Stable Bivalent Chromatin State

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