Telomeric transcriptional silencing in a natural context

Vega-Palas, Miguel A.; Venditti, Sabrina; E, Di Mauro

doi:10.1038/ng0397-232

Cited by 38 publications

(40 citation statements)

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“…In FSHD, telomere length influences expression of DUX4 and FRG2 (FSHD region gene 2) (Stadler et al 2013), suggesting that this region is sensitive to TPE. This is similar to studies in budding yeast in which telomeres can exert their repressive influence well beyond the immediate subtelomeric region (Maillet et al 1996;Vega-Palas et al 1997;Fourel et al 1999). So far, only a few endogenous genes have been reported to be influenced by TPE in human cells and tissues (Lou et al 2009;Boussouar et al 2013), but based on microarray analyses, there are likely to be hundreds of genes near telomeres that are modified by a telomere length-dependent and DNA damage-independent mechanism, termed telomere position effect-over long distance (TPE-OLD) .…”

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confidence: 62%

SORBS2transcription is activated by telomere position effect–over long distance upon telomere shortening in muscle cells from patients with facioscapulohumeral dystrophy

et al. 2015

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DNA is organized into complex three-dimensional chromatin structures, but how this spatial organization regulates gene expression remains a central question. These DNA/chromatin looping structures can range in size from 10-20 kb (enhancers/repressors) to many megabases during intra-and inter-chromosomal interactions. Recently, the influence of telomere length on chromatin organization prior to senescence has revealed the existence of long-distance chromatin loops that dictate the expression of genes located up to 10 Mb from the telomeres (Telomere Position Effect-Over Long Distances [TPE-OLD]). Here, we demonstrate the existence of a telomere loop at the 4q35 locus involving the sorbin and SH3 domain-containing protein 2 gene, SORBS2, a skeletal muscle protein using a modification of the chromosome conformation capture method. The loop reveals a cis-acting mechanism modifying SORBS2 transcription. The expression of this gene is altered by TPE-OLD in myoblasts from patients affected with the age-associated genetic disease, facioscapulohumeral muscular dystrophy (FSHD1A, MIM 158900). SORBS2 is expressed in FSHD myoblasts with short telomeres, while not detectable in FSHD myoblasts with long telomeres or in healthy myoblasts regardless of telomere length. This indicates that TPE-OLD may modify the regulation of the 4q35 locus in a pathogenic context. Upon differentiation, both FSHD and healthy myotubes express SORBS2, suggesting that SORBS2 is normally up-regulated by maturation/differentiation of skeletal muscle and is misregulated by TPE-OLD-dependent variegation in FSHD myoblasts. These findings provide additional insights for the complexity and age-related symptoms of FSHD.

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Section: [Supplemental Materials Is Available For This Article]supporting

confidence: 62%

SORBS2transcription is activated by telomere position effect–over long distance upon telomere shortening in muscle cells from patients with facioscapulohumeral dystrophy

et al. 2015

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“…Our results further suggest that the physical interaction between HML silencers and the III-L subtelomeric region contribute to efficient silencing of the Ty5 retrotransposon (46). Given that a GATC site located between telomere III-L and HML is not affected by the presence of HML silencers (Fig.…”

Section: Discussionmentioning

confidence: 67%

A Methyltransferase Targeting Assay Reveals Silencer-Telomere Interactions in Budding Yeast

Lebrun

Fourel

Defossez

et al. 2003

Molecular and Cellular Biology

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We have designed a modified version of the Dam identification technique and used it to probe higher-order chromatin structure in Saccharomyces cerevisiae. We fused the bacterial DNA methyltransferase Dam to the DNA-binding domain of TetR and targeted the resulting chimera to Tet operators inserted in the yeast genome at the repressed locus HML. We then monitored the methylation status of HML and other sequences by a quantitative technique combining methylation-sensitive restriction and real-time PCR. As expected, we found that TetR-Dam efficiently methylated HML in cis. More strikingly, when TetR-Dam was present at HML, we observed increased methylation in the III-L subtelomeric region but not in intervening sequences. This effect was lost when the HML silencers were inactivated by mutations. When the HM silencers and the Tet operators were transferred to a plasmid, strong methylation was clearly observed not only in the III-L subtelomeric region but also at other telomeres. These data indicate that HM silencers can specifically associate with telomeres, even those located on different chromosomes.

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“…A previous report has described that the Ty5-1 retrotransposon, a subtelomeric transcriptional unit located in S. cerevisiae LIII, undergoes telomeric silencing (19). This retrotransposon is silenced in wild-type strains but is derepressed in a sir3 mutant.…”

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Heterochromatin Organization of a Natural Yeast Telomere

Vega-Palas¹,

Venditti²,

Mauro³

1998

Journal of Biological Chemistry

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We have defined the in vivo heterochromatin structure of the left telomere of Saccharomyces cerevisiae chromosome III (LIII). Analysis of heterochromatin of a single telomere was so far lacking, due to the difficulties intrinsic to the highly repetitive nature of telomeric sequences. In LIII, the terminal (C 1-3 A) n repetitive sequences are followed by a complete X element and by the single copy Ty5-1 retrotransposon. Both the telosome and the X element exhibit overall resistance to micrococcal nuclease digestion reflecting their tight chromatin structure organization. The X element contains protein complexes and irregularly distributed but well localized nucleosomes. In contrast, a regular array of phased nucleosomes is associated with the promoter region of Ty5-1 and with the more centromere-proximal sequences. The lack of a structural component of yeast telomeres, the SIR3 protein, does not alter the overall tight organization of the X element but causes a nucleosome rearrangement within the promoter region of Ty5-1 and releases Ty5-1 silencing. Thus, Sir3p links the modification of the heterochromatin structure with loss of transcriptional silencing.Telomeres play an essential role in cell biology in stabilizing chromosomes and facilitating complete replication of chromosomal termini. Telomeric DNA usually contains tandem repetitions of a short motif flanked by subtelomeric middle repetitive sequences (1). In yeast, telomeric sequences are composed of about 350 base pairs containing the (C 1-3 A) n repeats and are followed by two main subtelomeric sequences: the YЈ and X elements (2). Y elements are highly conserved and are found in about 70% of the telomeres (2-5). X elements are present in all telomeres and can exist in two main forms: a complete form containing the X core and the STR-A,B,C,D (6) elements or a short form containing essentially the X core or part of it (2, 4 -6). The complete X is found in about 80% of the telomeres, whereas uncomplete forms are found in the remaining 20%.Previous reports have referred to the chromatin structure of yeast telomeres as heterochromatin. This denomination is based on structural and functional similarities that yeast telomeres share with Drosophila heterochromatin (7-9). In Saccharomyces cerevisiae the terminal (C 1-3 A) n repeats are organized into a nuclease-resistant structure called telosome (10, 11) that does not contain nucleosomes and is associated with the protein RAP1 (10 -13). This protein binds to the repetitive (C 1-3 A) n sequences (14, 15) and interacts with other proteins including RIF1, RIF2, SIR3,. The proteins SIR3 and SIR4 interact with each other, RAP1, and the amino terminus of the histones H3 and H4. Thus, the building of the telomeric heterochromatic structures in yeast involves complex homotypic and heterotypic interactions.Although the chromatin structure of yeast telomeres is probably the best known among all eukaryotes, its specific organization is still poorly understood. It is known that both YЈ and X elements contain nucleosomes (1...

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Telomeric transcriptional silencing in a natural context

Abstract: [No abstract available

Cited by 38 publications

References 15 publications

SORBS2transcription is activated by telomere position effect–over long distance upon telomere shortening in muscle cells from patients with facioscapulohumeral dystrophy

SORBS2transcription is activated by telomere position effect–over long distance upon telomere shortening in muscle cells from patients with facioscapulohumeral dystrophy

A Methyltransferase Targeting Assay Reveals Silencer-Telomere Interactions in Budding Yeast

Heterochromatin Organization of a Natural Yeast Telomere

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