FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2098494628> ?p ?o ?g. }

• W2098494628 endingPage "2161" @default.
• W2098494628 startingPage "2149" @default.
• W2098494628 abstract "Focus Review23 July 2009free access Silent chromatin at the middle and ends: lessons from yeasts Marc Bühler Corresponding Author Marc Bühler Epigenetics Focal Area, Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland Search for more papers by this author Susan M Gasser Corresponding Author Susan M Gasser Epigenetics Focal Area, Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland Search for more papers by this author Marc Bühler Corresponding Author Marc Bühler Epigenetics Focal Area, Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland Search for more papers by this author Susan M Gasser Corresponding Author Susan M Gasser Epigenetics Focal Area, Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland Search for more papers by this author Author Information Marc Bühler 1 and Susan M Gasser 1 1Epigenetics Focal Area, Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland *Corresponding authors. Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, Basel 4058, Switzerland. Tel.: +41 61 697 7255; Fax: +41 61 697 3976; E-mail: [email protected] or E-mail: [email protected] The EMBO Journal (2009)28:2149-2161https://doi.org/10.1038/emboj.2009.185 PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Eukaryotic centromeres and telomeres are specialized chromosomal regions that share one common characteristic: their underlying DNA sequences are assembled into heritably repressed chromatin. Silent chromatin in budding and fission yeast is composed of fundamentally divergent proteins tat assemble very different chromatin structures. However, the ultimate behaviour of silent chromatin and the pathways that assemble it seem strikingly similar among Saccharomyces cerevisiae (S. cerevisiae), Schizosaccharomyces pombe (S. pombe) and other eukaryotes. Thus, studies in both yeasts have been instrumental in dissecting the mechanisms that establish and maintain silent chromatin in eukaryotes, contributing substantially to our understanding of epigenetic processes. In this review, we discuss current models for the generation of heterochromatic domains at centromeres and telomeres in the two yeast species. Introduction Centromeres The centromere is essential for proper segregation of chromosomes in mitosis and meiosis and is therefore of vital importance for genetic stability. It is the DNA region in which the kinetochore is formed, a structure that allows chromosomes to associate with spindle microtubules. Centromere function and its many associated proteins are conserved, yet centromere specification is not always hard-wired to the DNA sequence and displays dramatic plasticity (reviewed in Sullivan et al, 2001; Allshire and Karpen, 2008). Centromeres can have different structures depending on their size, the number of kinetochore microtubules they interact with and whether or not they are surrounded by pericentric heterochromatin. Both Schizosaccharomyces pombe (S. pombe) and Saccharomyces cerevisiae (S. cerevisiae) are monocentric eukaryotes with localized centromeres, in contrast to holocentric organisms such as Caenorhabditis elegans, in which kinetochores form along the entire chromosome. A conserved feature of all centromeres is the special histone H3 variant, called Cnp1 in S. pombe and Cse4 in S. cerevisiae, which is found exclusively within the core centromeric region (Smith, 2002). In most other aspects, budding and fission yeast centromeres are quite different. In S. cerevisiae, complete centromere function is specified by only 125 bp of DNA comprising three distinct centromeric DNA elements (CDE I, II and III). The 15 bp of CDE III is most important as it attracts a complex containing sequence-specific DNA-binding proteins (Ndc10, Cep3, Ctf13 and Skp1). This complex dictates the assembly of the single Cse4-containing nucleosome, which spans the middle AT-rich CDEII element (Meluh et al, 1998; Furuyama and Biggins, 2007). Directly analogous elements are absent in S. pombe. Rather, centromere structure comprises a central core domain (cnt) bearing Cnp1 nucleosomes surrounded by a long inverted repeat. Each centromeric flank can be divided into two regions: the inner repeats (imr), which are specific to each of the three centromeres, and the outer repeats (otr), which are composed of elements known as dg and dh (Bjerling and Ekwall, 2002). The arrangement of dg and dh repeats with respect to each other and to the central core differs at each of the three fission yeast centromeres. Notably, the otr regions in S. pombe are assembled into silent heterochromatin, which is important for proper centromere function (see also accompanying Focus Review by Torras-Llort et al). Telomeres The telomere assumes a ‘cap’ structure that maintains and protects the ends of eukaryotic linear chromosomes (Zakian, 1996). Telomeres impede chromosomal fusion (end-to-end joining) by blocking activation of the DNA damage checkpoint response and locally impairing double-strand break repair. Most importantly, telomeres and the RNA-directed enzyme telomerase ensure the addition of TG repeats that are otherwise eroded with each successive round of cell division. Collectively, these functions stabilize chromosome ends and contribute to genomic stability. Importantly, the telomeres of both budding and fission yeasts are assembled into silent chromatin structures (Huang, 2002; see also accompanying Focus Review by Luke and Lingner). Telomeric DNA consists of three main parts: a short single-stranded (ss) 3′ overhang, double-stranded (ds) telomeric repeats and the subtelomeric region. The ss overhang and double-stranded stretch in S. cerevisiae comprise ∼300 bp of an irregular TG1−3 repeat that lies terminal to subtelomeric sequences. The subtelomeric regions include up to four tandem copies of Y′ elements, short internal TG1−3 repeats and an X element composed of imperfect repeats and a conserved 437 bp core (Zakian, 1996). The telomeric repeats of S. pombe are also 300 bp long, but are somewhat more degenerate. They consist mainly of TTACA(G)n (where n=1–8), and contain interspersed repeats of TTACGG and TTACACGG, each with two Gs. The repeats at both ends of chromosome III are immediately flanked by repeats of ribosomal RNA genes, whereas chromosomes I and II share similar subtelomeric sequences that contain open reading frames (ORFs). Telomere-linked helicases (tlh) are encoded by the most distal ORFs in the subtelomeric regions of chromosomes I (tlh1+) and II (tlh2+). These putative helicases are members of the recQ family and display extensive sequence homology with the dh and dg repeats found at centromeres (cenH like)(Wood et al, 2002; Mandell et al, 2005). Interestingly, the S. cerevisiae Y′ elements also encode a DNA helicase, which is expressed primarily in meiosis (Louis and Haber, 1992; Yamada et al, 1998). In S. pombe, there is conservation among neighbouring ORFs in addition to the homology shared by tlh1+ and tlh2+, indicating that the two subtelomeric regions resulted from a duplication. Although the terminal telomere sequence is associated with non-histone proteins forming a ‘telosome’, subtelomeric regions in both fission and budding yeast are nucleosomal (Vega-Palas et al, 1998; Wiren et al, 2005). Important is the presence, or absence, of post-translational modifications on the histone tails of subtelomeric nucleosomes. In S. cerevisiae, lysines at positions 9, 14, 18, 23 and 27 on H3, at positions 5, 8, 12 and 16 on H4, at position 7 on H2A, and at positions 11 and 16 on H2B are hypoacetylated in subtelomeric chromatin (Thompson et al, 1994; Braunstein et al, 1996; Suka et al, 2001). Moreover, two specific and universally conserved marks of active or open chromatin, H3K4me and H4K16ac, are absent from telomeres in both yeasts. Although S. cerevisiae has no H3K9me at all, this modification is characteristically present throughout fission yeast heterochromatin, including pericentric DNA, subtelomeric domains and at silent mating-type loci (Nakayama et al, 2001). Nucleosomes bearing H3K9me are also typically hypoacetylated on H4K16 and H3K14. In budding yeast, the hypoacetylated status of histone tails seems to be sufficient to favour the binding of the silent information regulatory (SIR) complex, Sir2-3-4, which in turn ensures a heritable downregulation of transcription of subtelomeric genes. This is called telomeric position effect, or TPE (see below). Sir2, a conserved NAD-dependent histone deacetylase, can act on all lysines of the H3 and H4 tails, but particularly targets H4K16ac (Blander and Guarente, 2004), as well as H3K9ac in S. pombe (Shankaranarayana et al, 2003). Other markers of active chromatin, notably di- and tri-methylated forms of histone H3K79, antagonize the binding of the SIR complex and impair repression of subtelomeric genes (van Leeuwen et al, 2002). Thus, the predominant pattern of histone modification at budding yeast telomeres is an absence of active marks, whereas S. pombe requires the positive signal provided by H3K9me. Intriguingly, in fission yeast Sir2 cooperates with Clr3 to eliminate acetylation marks on both H4K16, H3K9 and K14, which allows for subsequent methylation of H3K9 (Wiren et al, 2005). In addition to subtelomeric histones, a sequence-specific factor binds the TG-rich telomeric repeats. In almost every species these repeat-binding factors share a myb-like DNA-binding domain (Konig and Rhodes, 1997). In budding yeast, the terminal repeats are bound by the repressor activator protein 1 (Rap1), whereas in S. pombe the analogous protein is called Taz1. In addition, S. pombe, similar to man, has a Rap1 homologue that lacks the DNA-binding domain. Fission yeast Rap1 associates with telomeric repeats through Taz1, again analogous to the association of human Rap1 with Trf1. The additional telomere-associated proteins can be divided into two classes: those that mediate end maintenance by controlling telomerase accessibility, and those that promote silent chromatin. Ku, a heterodimer that binds all DNA ends regardless of sequence, has a special role at telomeres: it contributes both to controlling telomerase and to promoting silent chromatin. In addition, budding yeast Ku has a crucial role in anchoring telomeres to the nuclear envelope (NE), which further facilitates the nucleation and spread of chromatin-mediated gene silencing (see below) (Hediger et al, 2002; Taddei et al, 2004, 2009). In the absence of yKu, TG repeats in yeast shorten, subtelomeric repression is lost and strains become temperature sensitive (Fisher and Zakian, 2005). The epigenetic nature of centromeres and telomeres Epigenetics is the study of heritable changes in gene function that occur without a change in the sequence of the DNA. Centromere assembly and propagation provide a unique example of an epigenetic process as protein structures are assembled onto DNA and then stably propagated through numerous cell divisions in a DNA sequence independent manner. Despite their variation in size and sequence composition, the epigenetic aspect of centromeres is highly conserved. The epigenetic nature of centromeres is manifest in the fact that—although there are different requirements for centromere establishment—a functional centromere is transmitted epigenetically to daughter cells. Even the S. cerevisiae centromere shows epigenetic behaviour. Specifically, mutations in certain kinetochore proteins were shown to abolish de novo establishment of the S. cerevisiae centromere, although functional centromeres could be stably propagated for over 25 generations in this background (Mythreye and Bloom, 2003). Moreover, mutations in the core CDE element reduced the association of cohesin with naïve centromeres, but had little effect on established centromeres (Tanaka et al, 1999). In S. pombe, plasmids with minimal centromeric DNA establish functional centromeres stochastically, but once the functional state is attained it is propagated faithfully (Steiner and Clarke, 1994). Finally, a recent study also showed that heterochromatin and RNA interference (RNAi) are required to establish, but not to maintain, CENP-ACnp1 chromatin at fission yeast centromeres (Folco et al, 2008). Whether the telomeric functions of capping and end-replication behave epigenetically is unclear, yet telomere-associated gene silencing is one of the classic examples of semi-stable, yet heritable, transcriptional repression (Figure 1) (Gottschling et al, 1990). Both native subtelomeric genes and reporters integrated into telomere proximal zones succumb to transcriptional silencing through chromatin-mediated mechanisms. Despite the fact that the subtelomeric repression of transcription in budding and fission yeast share many heterochromatin-like features, the molecular mechanisms of repression differ significantly, as explained below. Figure 1.Variegated expression of a gene on packaging into a heterochromatic structure. (A) Cells expressing the wild-type ADE2 gene from its endogenous, euchromatic locus produce colonies that are white, (B) whereas those lacking the ADE2 gene appear red. (C) Juxtaposition of ADE2 to heterochromatin results in its silencing without changing the underlying coding sequence. Although inherited, the packaging state of ADE2 (euchromatic versus heterochromatic) can switch at a low frequency. This results in a variegating phenotype in a clonal population of cells. An example of a telomeric position effect (TPE) (Gottschling et al, 1990) in S. cerevisiae is shown here. Download figure Download PowerPoint Position effect variegation Position effect variegation (PEV) is a universally conserved epigenetic phenomenon through which inserted or translocated genes are influenced by nearby heterochromatin. Thereafter, the ensuing expression status of the gene is clonally inherited. Importantly, centromeric heterochromatin and PEV are only observed in organisms that have extensive domains of repetitive DNA at their centromeres. Thus, the 125-bp centromere of S. cerevisiae is not heterochromatic, and does not silence genes. On the other hand, in fission yeast reporter genes inserted in the centromeric regions cnt, imr and otr are subject to PEV (Allshire et al, 1994, 1995). Depending on the centromeric region, repression of the reporter is more or less pronounced. In the outer repeats, marker genes are tightly repressed, whereas marker genes inserted within the central core or the inner most repeats display a more variegated pattern of expression. The impact of local context on gene silencing is a conserved feature of PEV, which ensures domain- rather than promoter-specific repression. Although budding yeast lacks centromeric PEV, similar events are observed at the silent mating-type loci and near telomeres. In both budding and fission yeast, epigenetic gene silencing is crucial for mating-type determination, as it guarantees that these single-celled organisms can switch mating-type (Rusche et al, 2003). In each species the haploid genome contains the information needed to form at least two different cell types. In budding yeast, one of the two sets of mating-type information must be kept transcriptionally silent in haploid cells, or else the haploid behaves as a diploid and is unable to mate. In other words, the cell assumes a ‘pseudo diploid’ character, suppressing the information needed to form a zygote, undergo meiosis and sporulate. Thus, the robustness of the species requires heritable repression of at least one set of mating-type determining genes. The mechanisms that ensure mating-type repression in budding yeast, also serve to mediate position-dependent repression at telomeres (Aparicio et al, 1991; reviewed in Huang, 2002; Rusche et al, 2003). In an analogous manner, mechanisms that repress recombination and transcription at fission yeast centromeres contribute to silencing at the mating-type locus and TPE. The repression of mating-type information in both species is robust and extremely stable, whereas TPE is strongly variegating. This variegation is manifest as an ability to switch at a low frequency between ‘on’ and ‘off’ states and then propagate either state for many generations (Figure 1). The other criteria that define epigenetic repression and which are fulfilled by flies, S. cerevisiae and S. pombe are as follows: correlation with an altered chromatin structure that spreads outwards from a site of nucleation, silencing independently of the promoter concerned; reduced accessibility for large molecules or complexes; presence of hypoacetylated histones and/or specific marks that bind structural chromatin components; an involvement of nucleosome-binding non-histone complexes that are limiting in abundance and show sensitivity to gene dosage; and heritability through either mitotic or meiotic division. Screens in flies, S. pombe, and S. cerevisiae have identified mutations that enhance or suppress heterochromatin-induced silencing, classically called E(var)s and Su(var)s (Muller, 1930; Wakimoto, 1998). Hundreds of suppressors of PEV have been identified to date, and these have proven to be useful tools to study heritable repression, as well as centromere and telomere biology (Allshire et al, 1995; Pidoux and Allshire, 2004). Some of the mutated genes encode for histone modifying enzymes, heterochromatin proteins (HPs) or histone variants (reviewed in Huang, 2002; Rusche et al, 2003). Notably, genetic approaches such as these have allowed the field to create a general definition of heterochromatin, although the molecular mechanisms may be clearly distinct in different organisms. Silent chromatin assembly in budding yeast The assembly of silent chromatin is a multistep process, starting with the nucleation of a nucleosome-binding repression complex at specific regulatory sequences and its subsequent spread into neighbouring sequences. Pioneering studies on the ordered assembly of silent chromatin have been carried out in S. cerevisiae and have provided a foundation for understanding epigenetic repression (reviewed in Rusche et al, 2003). In brief, the formation of silent chromatin in budding yeast requires the association of a heterotrimeric nucleosome-binding SIR complex that contains Sir2, Sir3 and Sir4 proteins in 1:1:1 stoichiometry (Cubizolles et al, 2006). The complex is recruited to DNA by interactions with proteins that bind to chromosome ends or to specific regulatory sites called silencers. At budding yeast telomeres, the SIR complex is recruited by Rap1 and the yKu heterodimer. The Rap1 protein binds once every 18 bp within the TG repeat, and each Rap1 molecule provides a binding site for Sir4 (Luo et al, 2002). Sir4 recruitment is further catalysed by the yKu70/80 heterodimer, which is associated with the telomere through its DNA-end-binding function independently of Sir4 (Gravel et al, 1998; Martin et al, 1999). Importantly, Sir4 binding to Rap1 is antagonized by Rif1/Rif2 (Mishra and Shore, 1999). Sir4 is necessary for the recruitment of the entire SIR complex, although once nucleated, excess Sir3 can propagate along nucleosomes without Sir4 (Hecht et al, 1996). Sir2's NAD-dependent histone deacetylase activity keeps telomeric nucleosomes in a hypoacetylated state (Imai et al, 2000). Sir2 binds neither DNA nor histones with high affinity, but once recruited by Sir4, Sir2-mediated deacetylation can create a high-affinity binding site for Sir3. Sir3 has dimerization capacity and in complex with Sir2-4, results in the spread of the SIR complex outward from the nucleation site (Hecht et al, 1996; Liaw and Lustig, 2006). Sir3 contributes to the specificity for deacetylated histone tails, whereas Sir4 enhances the affinity of the complex through its ability to bind DNA (Martino et al, 2009) (Figure 2). Figure 2.Silent chromatin assembly in budding and fission yeast. (A) Cis-acting DNA sequences (nucleation sites, yellow boxes) are necessary to nucleate assembly of silent chromatin. Trans-acting proteins that directly bind the nucleation sites are indicated. Nucleation sites at fission yeast centromeres are likely to exist, although they have not been identified to date (yellow boxes). Bidirectional transcription (indicated by black arrows) of cendg/dh/H-like sequences (red boxes) is thought to produce dsRNA, which is processed into siRNAs by the RNAi machinery in S. pombe. siRNAs are required at least for the initiation of heterochromatin assembly at the silent mating-type locus and in addition for the maintenance of heterochromatin at centromeres. (B) Sir3 and Sir4 have dimerization capacity that results in the spread of the SIR complex outward from the nucleation site. Sir3 contributes to the specificity for deacetylated histone tails, whereas Sir4 enhances the affinity of the complex through its ability to bind DNA. Sir2-mediated deacetylation keeps telomeric nucleosomes hypoacetylated creating a high-affinity binding site for Sir3. (C) In S. pombe, the RITS complex promotes Clr4-mediated H3K9 methylation by associating with nascent transcripts through siRNA base pairing, and with methylated H3K9 through the chromodomain of its Chp1 subunit. Low levels of H3K9 methylation are maintained in RNAi mutant cells by a yet to be identified alternative pathway (putative nucleation element, yellow box). Primary siRNAs originating from dsRNA formed by bidirectional transcription of a centromeric sequence could prime further dsRNA synthesis and secondary siRNA generation by recruiting the RDRC complex to the nascent transcript. This would allow the spreading of H3K9me away from the nucleation site. H3K9me is bound by the chromodomain proteins Chp1, Chp2 and Swi6. The binding of Chp2 to H3K9me results in the recruitment of the SHREC complex, which in turn deacetylates H3K14. For unknown reasons this reduces RNA Pol II occupancy. Download figure Download PowerPoint During the deacetylation reaction catalysed by Sir2, NAD is hydrolysed and generates a by-product called O-acetyl-ADP-ribose (O-AADPR; Tanny et al, 1999; Tanner et al, 2000). This by-product can enhance the stability of the SIR–nucleosomal complex and may provoke a conformational change of the SIR-bound nucleosomal fibre (Tanny et al, 1999; Tanner et al, 2000; Tanny and Moazed, 2001; Liou et al, 2005; Martino et al, 2009). Although these in vitro results are compelling, questions remain as how this works in vivo, because Sir2 deacetylation activity could be replaced in modified yeast by a class I catalytic domain that does not generate O-AADPR, with only minor loss of transcriptional repression (Chou et al, 2008). Transcriptional silencing itself is thought to arise from sterical hindrance of positive regulators of transcription, by the interaction of the SIR complex with nucleosomes (Hecht et al, 1995). SIR complex association also leads to the sequestration of the silent chromatin at the NE through association with Esc1 (Gartenberg et al, 2004; Taddei et al, 2004). Both the binding of the SIR complex to nucleosomes and the recruitment of silent chromatin to the NE, have been shown to render silent chromatin less accessible to the recombination machinery and to the action of enzymatic probes, such as a bacterial DNA methyltransferase or restriction endonucleases (Gottschling, 1992; Singh and Klar, 1992; Loo and Rine, 1994). Despite this sequestration, certain classes of DNA-binding proteins seem able to access silent chromatin. For example, recognition sites for the FLP and Cre recombinases located within budding yeast silent chromatin domains are accessible to these enzymes when expressed at high levels (Holmes and Broach, 1996; Cheng et al, 1998). Moreover, promoters within a silenced domain can remain accessible to proteins of the transcription machinery, although the factors that stimulate elongation seem to be excluded (Sekinger and Gross, 2001; Gao and Gross, 2008). Fission yeast heterochromatin may also be accessible to the transcription machinery, because heterochromatin defects have been attributed to specific RNA pol II mutants (Djupedal et al, 2005; Kato et al, 2005). In addition, small interfering RNAs (siRNAs) have been identified, which match pericentromeric heterochromatin (Reinhart and Bartel, 2002; Cam et al, 2005; Buhler et al, 2008). Consistently, it was shown that though transcription of the ‘forward’ strand of pericentric DNA repeats was inhibited by heterochromatin formation, the ‘reverse’ strand seemed to be transcribed equally in both wild-type and heterochromatin-deficient strains (Volpe et al, 2002). This might suggest that transcription can cooperate with RNA decay mechanisms to keep heterochromatic regions repressed. The implications of this are discussed in more detail below. Heterochromatin assembly in fission yeast The assembly of heterochromatin in fission yeast, similar to that in budding yeast, involves orchestrated changes in chromatin modifications. After deacetylation of the histone H3 N-terminus by the class I and II histone deacetylases Clr3 and Clr6 (homologs of the HDACs Hda1 and Rpd3, respectively), and the class III NAD-dependent deacetylase Sir2, the methyltransferase, Clr4, methylates histone H3 at lysine 9, creating a binding site for the Swi6, Chp1 and Chp2 chromodomain proteins (Grewal et al, 1998; Partridge et al, 2000; Nakayama et al, 2001; Bjerling et al, 2002; Shankaranarayana et al, 2003; Motamedi et al, 2008). Swi6 and Chp2 are homologous to HP1 proteins, a conserved family of chromatin factors that recognizes methylated H3K9 in all species (Jacobs et al, 2001; Jacobs and Khorasanizadeh, 2002). Similar to the SIR complex, sequential cycles of Swi6 binding and Clr4 recruitment have been proposed to mediate the spreading of H3K9 methylation along the chromatin fibre (Nakayama et al, 2001; Grewal and Moazed, 2003). Recent studies have begun to elucidate mechanistic details of assembly and maintenance of these heterochromatic structures. Specifically, it has been shown that the fission yeast chromodomain proteins Swi6, Chp1 and Chp2, although found at both centromeric and telomeric heterochromatin, contribute in distinct ways to heterochromatin assembly at these loci (Thon and Verhein-Hansen, 2000; Partridge et al, 2000, 2002). First, Chp1 contributes to de novo assembly at all sites of heterochromatin, yet contributes to the maintenance of repressed chromatin exclusively at centromeres (Sadaie et al, 2004). This may stem from the fact that different heterochromatic regions are more or less dynamic; centromeric domains seem to be less stable and more in need of establishment events. Much similar to the situation in S. cerevisiae, the nucleation of heterochromatin in fission yeast requires cis-acting recruitment events (Figure 2), such as the recruitment of S. pombe Rap1 by Taz1 (Kanoh and Ishikawa, 2001; Zhang et al, 2008). Again similar to S. cerevisiae, recruitment pathways are partially redundant: the Taz1–Rap1 interaction is compensated by a second Taz1-dependent pathway that nucleates methylation of H3K9 by Clr4 (Kanoh et al, 2005). At the mating-type locus, an element called REIII recruits ATF/CREB family proteins and helps to nucleate heterochromatin (Jia et al, 2004), whereas two further elements, REII and cenH elements (similar to dg and dh repeats found at the centromere) function cooperatively to enhance heterochromatin formation at the mating-type locus (Ayoub et al, 2000). The cis-acting nucleation sites at centromeres seem to be less well defined. Indeed, recent evidence suggests that transcription of pericentromeric dg and dh repeats has a critical function in heterochromatin assembly (Figure 2). It seems that, in addition to specific DNA sequences, transcription and/or non-coding RNAs (ncRNA) can provide an initial scaffold for the formation of heterochromatin (Cam et al, 2009). This observation, coupled with the fact that strains defective in RNA processing mechanisms compromise PEV (Buhler et al, 2007; Houseley et al, 2007; Murakami et al, 2007; Vasiljeva et al, 2008; Wang et al, 2008), have challenged the paradigm that heterochromatin excludes transcription. Transcriptional scaffolds for the assembly of silent chromatin Although it seems paradoxical, transcription may well be a prerequisite for the assembly and maintenance of some forms of silent chromatin. Although we know little about the underlying mechanisms that link RNA to chromatin, there is growing evidence that ncRNAs can contribute to epigenetic inheritance (Bernstein and Allis, 2005). One of the most prominent examples is the ncRNA Xist that is involved in X chromosome inactivation in mammalian females (Leeb et al, 2009; Senner and Brockdorff, 2009). Xist nucleates a repressive chromatin state in cis for almost an entire chromosome. ncRNAs have also been linked to certain forms of gene repression in budding yeast. For instance, a non-coding antisense RNA has been implicated in transcriptional silencing of Ty1 retrotransposons (Berretta et al, 2008), and antisense transcription has been shown to regulate chromatin-dependent silencing of the PHO84 gene in an aging yeast culture (Camblong et al, 2007). The PHO84 antisense RNA is normally kept at a low level by the nuclear exosome, an RNAse complex with 3′–5′ exonucleolytic activity. When this antisense RNA is degraded, PHO84 sense mRNA is present in maximal amounts, yet under stress conditions the antisense ncRNA accumulates and recruits the exosome to the PHO84 gene, reducing the sense message. The PHO84 ncRNA then seems to recruit a histone deacetylase to the locus to further inhibit sense transcription (Camblong et al, 2007). Alt" @default.
• W2098494628 created "2016-06-24" @default.
• W2098494628 creator A5080985969 @default.
• W2098494628 creator A5082924650 @default.
• W2098494628 date "2009-07-23" @default.
• W2098494628 modified "2023-09-26" @default.
• W2098494628 title "Silent chromatin at the middle and ends: lessons from yeasts" @default.
• W2098494628 cites W144423133 @default.
• W2098494628 cites W1528082486 @default.
• W2098494628 cites W1596438740 @default.
• W2098494628 cites W1647639606 @default.
• W2098494628 cites W1797040506 @default.
• W2098494628 cites W1822536792 @default.
• W2098494628 cites W1964170914 @default.
• W2098494628 cites W1964192379 @default.
• W2098494628 cites W1968055625 @default.
• W2098494628 cites W1970569685 @default.
• W2098494628 cites W1971279688 @default.
• W2098494628 cites W1972516690 @default.
• W2098494628 cites W1975290221 @default.
• W2098494628 cites W1978197643 @default.
• W2098494628 cites W1983636619 @default.
• W2098494628 cites W1985036194 @default.
• W2098494628 cites W1987362169 @default.
• W2098494628 cites W1987777159 @default.
• W2098494628 cites W1989753542 @default.
• W2098494628 cites W1990186602 @default.
• W2098494628 cites W1992350296 @default.
• W2098494628 cites W1992506108 @default.
• W2098494628 cites W1994900084 @default.
• W2098494628 cites W1995111407 @default.
• W2098494628 cites W1996047595 @default.
• W2098494628 cites W1997530113 @default.
• W2098494628 cites W1997630514 @default.
• W2098494628 cites W1997818262 @default.
• W2098494628 cites W1999284470 @default.
• W2098494628 cites W2000651503 @default.
• W2098494628 cites W2006094963 @default.
• W2098494628 cites W2006149421 @default.
• W2098494628 cites W2008123017 @default.
• W2098494628 cites W2010027764 @default.
• W2098494628 cites W2013755918 @default.
• W2098494628 cites W2013939194 @default.
• W2098494628 cites W2015735754 @default.
• W2098494628 cites W2020599848 @default.
• W2098494628 cites W2021432006 @default.
• W2098494628 cites W2024204233 @default.
• W2098494628 cites W2024295388 @default.
• W2098494628 cites W2026111974 @default.
• W2098494628 cites W2026344530 @default.
• W2098494628 cites W2026898742 @default.
• W2098494628 cites W2028795836 @default.
• W2098494628 cites W2029222292 @default.
• W2098494628 cites W2030776068 @default.
• W2098494628 cites W2031087599 @default.
• W2098494628 cites W2031098287 @default.
• W2098494628 cites W2032187789 @default.
• W2098494628 cites W2034235936 @default.
• W2098494628 cites W2034564804 @default.
• W2098494628 cites W2037104460 @default.
• W2098494628 cites W2037541952 @default.
• W2098494628 cites W2038175996 @default.
• W2098494628 cites W2038766179 @default.
• W2098494628 cites W2039675632 @default.
• W2098494628 cites W2039940539 @default.
• W2098494628 cites W2040234712 @default.
• W2098494628 cites W2040378600 @default.
• W2098494628 cites W2040542961 @default.
• W2098494628 cites W2045372653 @default.
• W2098494628 cites W2046393794 @default.
• W2098494628 cites W2049094938 @default.
• W2098494628 cites W2049376070 @default.
• W2098494628 cites W2049992533 @default.
• W2098494628 cites W2050066317 @default.
• W2098494628 cites W2052770408 @default.
• W2098494628 cites W2054600961 @default.
• W2098494628 cites W2055223560 @default.
• W2098494628 cites W2056827933 @default.
• W2098494628 cites W2057114955 @default.
• W2098494628 cites W2057777173 @default.
• W2098494628 cites W2058346978 @default.
• W2098494628 cites W2060390444 @default.
• W2098494628 cites W2061810442 @default.
• W2098494628 cites W2062779626 @default.
• W2098494628 cites W2065304353 @default.
• W2098494628 cites W2069080094 @default.
• W2098494628 cites W2069974281 @default.
• W2098494628 cites W2071391879 @default.
• W2098494628 cites W2071726225 @default.
• W2098494628 cites W2072540566 @default.
• W2098494628 cites W2073204556 @default.
• W2098494628 cites W2077412625 @default.
• W2098494628 cites W2077719564 @default.
• W2098494628 cites W2084293680 @default.
• W2098494628 cites W2084790740 @default.
• W2098494628 cites W2087529216 @default.
• W2098494628 cites W2088164618 @default.
• W2098494628 cites W2089661916 @default.

• next