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Long-Range Silencing and Position Effects at Telomeres and Centromeres: Parallels and Differences

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Long-Range Silencing and Position Effects at Telomeres and Centromeres: Parallels and Differences View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by RERO DOC Digital Library CMLS, Cell. Mol. Life Sci. 60 (2003) 2303–2318 1420-682X/03/112303-16 DOI 10.1007/s00018-003-3246-x CMLS Cellular and Molecular Life Sciences © Birkhäuser Verlag, Basel, 2003 Long-range silencing and position effects at telomeres and centromeres: parallels and differences S. Perrod and S. M. Gasser* University of Geneva, Department of Molecular Biology, Quai Ernest-Ansermet 30, 1211 Geneva 4 (Switzerland), Fax: +41 22 379 6868, e-mail [email protected] Abstract. Most of the human genome is compacted into dress the mechanisms of centromeric, telomeric and lo- heterochromatin, a form that encompasses multiple cus-specific gene silencing, comparing simple and com- forms of inactive chromatin structure. Transcriptional si- plex animals with yeast. Some aspects are universally lencing mechanisms in budding and fission yeasts have shared, such as histone-tail modifications, while others provided genetically tractable models for understanding are unique to either centromeres or telomeres. These may heritably repressed chromatin. These silent domains are reflect roles for heterochromatin in other chromosomal typically found in regions of repetitive DNA, that is, ei- functions, like kinetochore attachment and DNA ends ther adjacent to centromeres or telomeres or within the protection. tandemly repeated ribosomal DNA array. Here we ad- Key words. Silencing; PEV; yeast; SIR protein; epigenetics; Drosophila; telomeres; rDNA. Comparison of long-range silencing with generally refers to noncoding satellite repeats. Faculta- heterochromatin tive heterochromatin can be specific to one of two ho- mologous chromosomes, or to a certain cell type or de- Long-range silencing generates a heritable, transcription- velopmental stage, and leads to the repression of unique ally inactive chromatin structure that is associated with sequences rich in genes. Constitutive heterochromatin re- stable posttranslational modifications of histones, such as mains condensed in almost all somatic cells of a given methylation or hypoacetylation (for reviews [1–3]). Such organism and usually involves repetitive, noncoding repression is not promoter specific, but rather region spe- DNA sequences. Such gene-poor regions are typically, al- cific, and can act over large stretches of DNA. A re- though not exclusively, located near centromeres or pressed state can persist through meiotic and mitotic cell telomeres and can induce repression of nearby genes in divisions and usually leads to late replication in S phase. an epigenetic manner. This phenomenon is called posi- Whereas gene silencing shares the key properties of inac- tion effect variegation. The precise function of simple re- cessibility and epigenetic inheritance with heterochro- peat DNA is poorly understood, but it is likely to serve a matin, transcriptionally silent domains are not always cy- structural role in chromosome pairing and segregation tologically visible, even though this trait was traditionally (reviewed in [5, 6]), which only indirectly results in used to distinguish heterochromatin from euchromatin transcriptional silencing. Here we compare the silencing [4]. The absence of a cytologically distinct hetero-chro- that occurs in Saccharomyces cerevisiae (budding yeast) matin is particularly pronounced in budding yeasts, with the constitutive heterochromatin found at the cen- which nonetheless has provided a powerful model for tromeres of Schizosaccharomyces pombe (fission yeast) mechanisms of chromatin-mediated repression. and higher eukaryotes, like Drosophila and human beings It is helpful to distinguish different types of heterochro- (see fig. 1). By using ‘heterochromatin’ as a collective matin; the most common are called facultative (as in tis- term to describe a range of compact interphase chromatin sue-specific domain inactivation) and constitutive, which structures that are distinct from transcriptionally active and structurally accessible ‘euchromatin,’ we can indeed * Corresponding author. include silent loci in yeast in this category. 2304 S. Perrod and S. M. Gasser Long-range silencing and position effects Budding yeast silencing (homothallic mating-type locus left or right), (ii) telo- meres and (iii) the rDNA array (reviewed in [7, 8]). Genes Silent domains within S. cerevisiae chromosomes gener- located near or within these domains are either com- ally cover only a few kilobases, a distance that is not sur- pletely inert for transcription or exhibit a variegated state prising given the compact organization of the budding of repression that is relatively stable within a single cell. yeast genome. Except for the irregular TG repeat at Importantly, repression is position, and not promoter, telomeres, budding yeast lacks simple repeat DNA, and specific. Maintenance of silencing is essential for pre- genes have few introns and lie within 1–2 kb of each serving mating competence in yeast, because derepres- other. Perhaps because of the complexity and sheer size sion of the HM loci leads to expression of both mating- of higher eukaryotic genomes, many more proteins are type programs, allowing haploid cells to acquire the prop- implicated directly or indirectly in the formation of hete- erties of a nonmating diploid cell. On the other hand, the rochromatin in complex organisms than in yeast. Indeed, relaxation of silencing at the rDNA repeats leads to re- constitutive heterochromatin constitutes >30% of the combination and excision of rDNA repeats [9] which cor- genome in Drosophila and >55% in humans and mice, relates with a shortened life span [10]. In S. pombe (fis- whereas heritably silent chromatin represents <1% of the sion yeast), centromeres are composed of large repetitive total budding yeast genome. sequence elements that also confer position-dependent Nonetheless, three distinct chromosomal regions of S. repression of Pol II-transcribed genes. This centromere- cerevisiae confer a heritable state of transcriptional re- induced repression, although absent in budding yeast, is pression (i.e., epigenetic silencing) on otherwise func- the most widely conserved type of heterochromatin and tional promoters: (i) the mating-type loci HML and HMR thus will be examined first. Figure 1. Trans-acting factors required for repression. Top: Propagation of silencing at budding yeast telomeres and HM loci involves mul- tiple steps. Bottom: Key elements for targeting repression in diverse organisms. The cis-acting sequences necessary for the binding of trans- acting factors have not yet been determined for the budding yeast rDNA or for ribosomal repression or PEV in Drosophila. In fission yeast, siRNA are required at least for the initiation of repression and in addition for the maintenance of repression at centromeres. Only the se- quence of siRNA necessary for centromeric silencing is known. Localization of Swi6 at the silent mating-type locus and at centromeres requires Clr4/Rik1, Clr3/Clr6 and Chp1, whereas HP1 independently initiates methylation in a small domain of the chromocenter. CMLS, Cell. Mol. Life Sci. Vol. 60, 2003 Multi-author Review Article 2305 Centromeres cific variant [17]. Alternatively, a histone exchange factor may replace H3 with a H3 variant in a localized and repli- Repetitive centromeric sequences and centromeric cation-independent manner. identity The centromere is an essential chromosomal landmark that provides a site for the attachment of mitotic and mei- Pericentromeric heterochromatin mediates PEV otic spindle microtubules, which in turn mediate mitotic Pericentromeric heterochromatin and its associated phe- chromosome segregation. Centromeric activity in bud- nomenon of position-effect variegation (PEV) are only ding yeast is conferred by a specific sequence of roughly observed in organisms having large regional centromeres. 125 bp, whereas centromeres of fission yeast and higher A mere 125 bp is necessary and sufficient for the assem- eukaryotes are composed of large repetitive DNA do- bly of a functional S. cerevisiae centromere, and this se- mains packaged into a heterochromatic structure (for de- quence is not flanked by heterochromatin, nor does it si- tails see table 1; for centromere reviews [11, 12]). Be- lence genes. In contrast, now-classic studies by H. J. cause these ‘regional’ centromeres cannot be easily de- Müller (reviewed in [18, 19]) showed that Drosophila lineated on the basis of their sequence, it has been genes that were transposed by natural or induced genetic difficult to determine the minimal size of a functional rearrangements to sites near pericentric heterochromatin centromere in most organisms. frequently assume a variegated pattern of expression. In fission yeast, Drosophila and mammals, heterochro- This chromosomal position effect can spread over dis- matin is an integral part of the centromere, and the estab- tances of 1 Mbp or more, generally reflecting a gradient lishment and maintenance of heterochromatin correlates of gene inactivation that is inversely correlated with dis- with centromere function [5]. Centric heterochromatin tance [18]. Recent data show that the local context of a may not only provide a site for microtubule attachment, gene also influences the degree of PEV, and suggest that but may also contribute to the nucleation of sister chro- the repression process can also be discontinuous and matid cohesion [13]. The occasional creation of new cen- modulated by promoter strength [20]. Indeed,
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