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The 4q subtelomere harboring the FSHD locus is specifically anchored with peripheral heterochromatin unlike most human telomeres.

Tam R, Smith KP, Lawrence JB - J. Cell Biol. (2004)

Bottom Line: Studies of hybrid and translocation cell lines indicate this localization is inherent to the distal tip of 4q.However, consistent association of the pathogenic D4Z4 locus with the heterochromatic compartment supports a potential role in regulating the heterochromatic state and makes a telomere positioning effect more likely.Furthermore, D4Z4 repeats on other chromosomes also frequently organize with the heterochromatic compartment at the nuclear or nucleolar periphery, demonstrating a commonality among chromosomes harboring this subtelomere repeat family.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.

ABSTRACT
This paper investigates the nuclear localization of human telomeres and, specifically, the 4q35 subtelomere mutated in facioscapulohumeral dystrophy (FSHD). FSHD is a common muscular dystrophy that has been linked to contraction of D4Z4 tandem repeats, widely postulated to affect distant gene expression. Most human telomeres, such as 17q and 17p, avoid the nuclear periphery to reside within the internal, euchromatic compartment. In contrast, 4q35 localizes at the peripheral heterochromatin with 4p more internal, generating a reproducible chromosome orientation that we relate to gene expression profiles. Studies of hybrid and translocation cell lines indicate this localization is inherent to the distal tip of 4q. Investigation of heterozygous FSHD myoblasts demonstrated no significant displacement of the mutant allele from the nuclear periphery. However, consistent association of the pathogenic D4Z4 locus with the heterochromatic compartment supports a potential role in regulating the heterochromatic state and makes a telomere positioning effect more likely. Furthermore, D4Z4 repeats on other chromosomes also frequently organize with the heterochromatic compartment at the nuclear or nucleolar periphery, demonstrating a commonality among chromosomes harboring this subtelomere repeat family.

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Interphase telomere distribution. (A) Mammalian telomeres (red) distribute widely (blue, nucleolus; green, SC35 domains) with most avoiding the peripheral heterochromatin compartment. (B) Through focal series montage demonstrating the distribution of telomeres through the nucleus. Sections are 300 nm apart along the Z axis from the coverslip (top left) to the top of the cell (bottom right). The series was captured in wide field and deconvolved using a constrained iterative algorithm. Red, telomeres; green, nucleopores; blue, SC35 domains.
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fig2: Interphase telomere distribution. (A) Mammalian telomeres (red) distribute widely (blue, nucleolus; green, SC35 domains) with most avoiding the peripheral heterochromatin compartment. (B) Through focal series montage demonstrating the distribution of telomeres through the nucleus. Sections are 300 nm apart along the Z axis from the coverslip (top left) to the top of the cell (bottom right). The series was captured in wide field and deconvolved using a constrained iterative algorithm. Red, telomeres; green, nucleopores; blue, SC35 domains.

Mentions: To address whether the general distribution of human telomeres in primary myoblasts, muscle, and fibroblasts resembles the clustered peripheral distribution of yeast telomeres or is more internal as in transformed HeLa cells (Luderus et al., 1996), a PNA oligo probe to the TTAGGG repeat was hybridized (Fig. 2 A). Results show the majority (83%) of human telomeres to be in the nucleoplasm, clearly distant from the heterochromatic region encircling the nuclear periphery, as viewed in two dimensions. Although only 17% of telomeres were within 0.6 μm of the nuclear periphery, another 22% position at the nucleolus (largely accounted for by the 10 acrocentric chromosomes carrying rDNA genes). Optical sectioning of cultured muscle confirmed that the vast majority of telomeres are internal and do not abut the nuclear envelope in the X-Y or Z planes (Fig. 2 B). Interestingly, a number of telomeres are tightly juxtaposed to the splicing factor–rich SC35 domains. The ∼60–80 separate telomere signals observed suggests that telomere clustering was limited unlike in yeast, which is consistent with findings in HeLa cells (Nagele et al., 2001; Molenaar et al., 2003).


The 4q subtelomere harboring the FSHD locus is specifically anchored with peripheral heterochromatin unlike most human telomeres.

Tam R, Smith KP, Lawrence JB - J. Cell Biol. (2004)

Interphase telomere distribution. (A) Mammalian telomeres (red) distribute widely (blue, nucleolus; green, SC35 domains) with most avoiding the peripheral heterochromatin compartment. (B) Through focal series montage demonstrating the distribution of telomeres through the nucleus. Sections are 300 nm apart along the Z axis from the coverslip (top left) to the top of the cell (bottom right). The series was captured in wide field and deconvolved using a constrained iterative algorithm. Red, telomeres; green, nucleopores; blue, SC35 domains.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172553&req=5

fig2: Interphase telomere distribution. (A) Mammalian telomeres (red) distribute widely (blue, nucleolus; green, SC35 domains) with most avoiding the peripheral heterochromatin compartment. (B) Through focal series montage demonstrating the distribution of telomeres through the nucleus. Sections are 300 nm apart along the Z axis from the coverslip (top left) to the top of the cell (bottom right). The series was captured in wide field and deconvolved using a constrained iterative algorithm. Red, telomeres; green, nucleopores; blue, SC35 domains.
Mentions: To address whether the general distribution of human telomeres in primary myoblasts, muscle, and fibroblasts resembles the clustered peripheral distribution of yeast telomeres or is more internal as in transformed HeLa cells (Luderus et al., 1996), a PNA oligo probe to the TTAGGG repeat was hybridized (Fig. 2 A). Results show the majority (83%) of human telomeres to be in the nucleoplasm, clearly distant from the heterochromatic region encircling the nuclear periphery, as viewed in two dimensions. Although only 17% of telomeres were within 0.6 μm of the nuclear periphery, another 22% position at the nucleolus (largely accounted for by the 10 acrocentric chromosomes carrying rDNA genes). Optical sectioning of cultured muscle confirmed that the vast majority of telomeres are internal and do not abut the nuclear envelope in the X-Y or Z planes (Fig. 2 B). Interestingly, a number of telomeres are tightly juxtaposed to the splicing factor–rich SC35 domains. The ∼60–80 separate telomere signals observed suggests that telomere clustering was limited unlike in yeast, which is consistent with findings in HeLa cells (Nagele et al., 2001; Molenaar et al., 2003).

Bottom Line: Studies of hybrid and translocation cell lines indicate this localization is inherent to the distal tip of 4q.However, consistent association of the pathogenic D4Z4 locus with the heterochromatic compartment supports a potential role in regulating the heterochromatic state and makes a telomere positioning effect more likely.Furthermore, D4Z4 repeats on other chromosomes also frequently organize with the heterochromatic compartment at the nuclear or nucleolar periphery, demonstrating a commonality among chromosomes harboring this subtelomere repeat family.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.

ABSTRACT
This paper investigates the nuclear localization of human telomeres and, specifically, the 4q35 subtelomere mutated in facioscapulohumeral dystrophy (FSHD). FSHD is a common muscular dystrophy that has been linked to contraction of D4Z4 tandem repeats, widely postulated to affect distant gene expression. Most human telomeres, such as 17q and 17p, avoid the nuclear periphery to reside within the internal, euchromatic compartment. In contrast, 4q35 localizes at the peripheral heterochromatin with 4p more internal, generating a reproducible chromosome orientation that we relate to gene expression profiles. Studies of hybrid and translocation cell lines indicate this localization is inherent to the distal tip of 4q. Investigation of heterozygous FSHD myoblasts demonstrated no significant displacement of the mutant allele from the nuclear periphery. However, consistent association of the pathogenic D4Z4 locus with the heterochromatic compartment supports a potential role in regulating the heterochromatic state and makes a telomere positioning effect more likely. Furthermore, D4Z4 repeats on other chromosomes also frequently organize with the heterochromatic compartment at the nuclear or nucleolar periphery, demonstrating a commonality among chromosomes harboring this subtelomere repeat family.

Show MeSH
Related in: MedlinePlus