Silencing: the establishment and inheritance of stable, repressed transcription states

Rivier, David H.; Rine, Jasper

doi:10.1016/s0959-437x(05)80286-2

Cited by 43 publications

(18 citation statements)

References 48 publications

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“…16,1996 HISTONE DEACETYLASE INHIBITORS AND CELL SENESCENCE 5215 vate a cell cycle checkpoint) would be by impairing the stability of heterochromatin-like chromatin structures. Such structures are implicated in the developmental control of differentiation and, importantly, in specific cases appear to persist by virtue of a memory mechanism(s) (44,58,59,63,69,71). A striking feature of heterochromatin-like regions in mammalian cells is the underacetylation of selected lysine residues in histone H4 (40); accordingly, proper function of histone deacetylase is assumed to be required for the reformation of these regions during the latter part of each cell cycle (2).…”

Section: Discussionmentioning

confidence: 99%

Human Fibroblast Commitment to a Senescence-Like State in Response to Histone Deacetylase Inhibitors Is Cell Cycle Dependent

Ogryzko

Hirai

Russanova

et al. 1996

Molecular and Cellular Biology

243

153

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Human diploid fibroblasts (HDF) complete a limited number of cell divisions before entering a growth arrest state that is termed replicative senescence. Two histone deacetylase inhibitors, sodium butyrate and trichostatin A, dramatically reduce the HDF proliferative life span in a manner that is dependent on one or more cell doublings in the presence of these agents. Cells arrested and subsequently released from histone deacetylase inhibitors display markers of senescence and exhibit a persistent G 1 block but remain competent to initiate a round of DNA synthesis in response to simian virus 40 T antigen. Average telomere length in prematurely arrested cells is greater than in senescent cells, reflecting a lower number of population doublings completed by the former. Taken together, these results support the view that one component of HDF senescence mimics a cell cycle-dependent drift in differentiation state and that propagation of HDF in histone deacetylase inhibitors accentuates this component.Cellular senescence in human diploid fibroblasts (HDF) and other human cell types has been extensively studied (17,26,35,53,73,85) yet remains incompletely understood. On the basis of current knowledge, it is not unreasonable to suppose that multiple mechanisms contribute to the senescence phenotype and that the relative contributions of such mechanisms may vary for different cell types and conditions of cell propagation. At least two senescence-associated changes, increased oxidative stress (74, 75) and telomere shortening (33,34,55,87), have been intensively studied and are widely viewed as important components of in vitro aging. Less well studied is a third aspect of senescence, namely, its apparent relatedness to differentiation (4,16,26,48,57). Although these two processes are not necessarily synonymous (60, 88), in many respects senescence resembles a partial or aberrant form of terminal differentiation, with cells appearing to acquire a phenotype that is suboptimal for tissue function and maintenance. HDF proliferative potential is dependent primarily on the number of rounds of DNA synthesis completed rather than the cumulative time in culture (17,19,27); thus, to the extent that senescence is akin to terminal differentiation, it most closely resembles model systems (e.g., murine erythroleukemia or promyelocytic leukemia cells) where a requirement for passage through the cell cycle has been demonstrated (7,45,46).Our attention to the differentiative aspects of senescence was first prompted by experiments designed to compare cell cycle arrest mechanisms in senescent and quiescent cells. Transient expression of simian virus 40 (SV40) T antigen is strongly mitogenic, i.e., is dominant over cell cycle arrest mechanisms, in both senescent cells and serum-deprived quiescent fibroblasts (29,39,80). We and others observed that in senescent HDF, but not quiescent cells, the domain in T antigen which mediates binding to retinoblastoma (Rb) family proteins is required for efficient stimulation of DNA synthesis (8a, 65). This...

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Section: Discussionmentioning

confidence: 99%

Human Fibroblast Commitment to a Senescence-Like State in Response to Histone Deacetylase Inhibitors Is Cell Cycle Dependent

Ogryzko

Hirai

Russanova

et al. 1996

Molecular and Cellular Biology

243

153

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“…Yet when one examines these same sequences on the chromosome by two-dimensional gel electrophoresis, to detect structures characteristic of the presence of an origin of DNA replication, neither HML-E nor HML-I is active, while HMR-E does appear to act as a chromosomal origin, although only in a fraction of cell cycles (Dubey et al 1991;Rivier and Rine 1992;Collins and Newlon 1994). Whether silencing depends on origin activity has been the subject of much debate; current evidence suggests that the binding of the ORC proteins to silencer regions is a key step in establishing silencing, but it is not necessary that replication be initiated at that site (Fox et al 1993;Ehrenhofer-Murray et al 1995;Fox et al 1997;Li et al 2001).…”

Section: Cis-acting Silencer Sequencesmentioning

confidence: 99%

Mating-Type Genes andMATSwitching inSaccharomyces cerevisiae

2012

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Mating type in Saccharomyces cerevisiae is determined by two nonhomologous alleles, MATa and MATa. These sequences encode regulators of the two different haploid mating types and of the diploids formed by their conjugation. Analysis of the MATa1, MATa1, and MATa2 alleles provided one of the earliest models of cell-type specification by transcriptional activators and repressors. Remarkably, homothallic yeast cells can switch their mating type as often as every generation by a highly choreographed, site-specific homologous recombination event that replaces one MAT allele with different DNA sequences encoding the opposite MAT allele. This replacement process involves the participation of two intact but unexpressed copies of mating-type information at the heterochromatic loci, HMLa and HMRa, which are located at opposite ends of the same chromosome-encoding MAT. The study of MAT switching has yielded important insights into the control of cell lineage, the silencing of gene expression, the formation of heterochromatin, and the regulation of accessibility of the donor sequences. Real-time analysis of MAT switching has provided the most detailed description of the molecular events that occur during the homologous recombinational repair of a programmed double-strand chromosome break. TABLE OF CONTENTS Abstract 33Introduction 34

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“…HML and HMR loci are constitutively repressed in wild-type cells. However, conditional alleles of the SIR genes have led to a greater understanding of heterochromatin establishment, loss, and maintenance (5)(6)(7)(8)(9). Investigating the dynamics of transitions between heterochromatin and euchromatin in mutants with altered chromatin structure should reveal how chromatin modifications impact the formation of these two states.…”

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confidence: 99%

Symmetry, asymmetry, and kinetics of silencing establishment in Saccharomyces cerevisiae revealed by single-cell optical assays

Osborne

Hiraoka²,

Rine³

2011

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

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In Saccharomyces cerevisiae, silent chromatin inhibits the expression of genes at the HML, HMR, and telomeric loci. When silent chromatin forms de novo, the rate of its establishment is influenced by different chromatin states. In particular, loss of the enzyme Dot1, an H3 K79 methyltransferase, leads to rapid silencing establishment. We tested whether silencing establishment was antagonized by H3 K79 methylation or by the Dot1 protein itself competing with Sir3 for binding sites on nucleosomes. To do so, we monitored fluorescence activity in cells containing a GFP gene within the HML locus during silencing establishment in a series of dot1 and histone mutant backgrounds. Silencing establishment rate was correlated with Dot1's enzymatic function rather than with the Dot1 protein itself. In addition, histone mutants that mimicked the conformation of unmethylated H3 K79 increased the rate of silencing establishment, indicating that the H3 K79 residue affected silencing independently of Dot1 abundance. Using fluorophore-based reporters, we confirmed that mother and daughter cells often silence in concert, but in instances where asymmetric silencing occurs, daughter cells established silencing earlier than their mothers. This noninvasive technique enabled us to demonstrate an asymmetry in silencing establishment of a key regulatory locus controlling cell fate.

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Silencing: the establishment and inheritance of stable, repressed transcription states

Cited by 43 publications

References 48 publications

Human Fibroblast Commitment to a Senescence-Like State in Response to Histone Deacetylase Inhibitors Is Cell Cycle Dependent

Human Fibroblast Commitment to a Senescence-Like State in Response to Histone Deacetylase Inhibitors Is Cell Cycle Dependent

Mating-Type Genes andMATSwitching inSaccharomyces cerevisiae

Symmetry, asymmetry, and kinetics of silencing establishment in Saccharomyces cerevisiae revealed by single-cell optical assays

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