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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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The 4q telomere favors the heterochromatic compartment and, in particular, the nuclear periphery. This specific localization is striking when compared to other loci on chromosome 4 and to other telomeres. (A) The 4q35 (red, arrows) is found at either the nuclear periphery or next to the nucleolus as demarcated by fibrillarin (blue) in this fibroblast. (B) 4q35 (red, arrows) localizes within the peripheral rim (DAPI, blue) defined by depletion of hnRNA (green). (C) The peripheral localization of 4q (red) contrasts with the internal localization of 4p (green). Lamin A and nucleoli were detected simultaneously (blue). (D) The centromere of chromosome 4 (green) favors the nucleolus (blue), whereas the 4q telomere (red) is oriented at the periphery. (E) Analysis of three 4q subtelomeric probes reveals no preferred ordering between these three loci with respect to the periphery. RP11-279K24 (red) is more peripheral than RP11-597P9 (green) in one allele in contrast to the loci at the other allele. (F) Likewise, RP11-279K24 (red) is more peripheral than D4Z4 (green) in one allele in contrast to the other. (G) Chromosome 17q (red) and 17p (green) avoid the nuclear periphery and are often in the vicinity of the nucleolus (blue), particularly in myotubes. (H) The 17q (red) telomere frequently colocalizes with SC35 domains (blue) in a myoblast. (I) Quantitative distributions of total or specific telomeres (or centromere) in myoblasts. We analyzed 1,000 total telomeres, >800 4q, 200 4p, 200 4cen, 100 17p, and 100 17q signals.
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fig3: The 4q telomere favors the heterochromatic compartment and, in particular, the nuclear periphery. This specific localization is striking when compared to other loci on chromosome 4 and to other telomeres. (A) The 4q35 (red, arrows) is found at either the nuclear periphery or next to the nucleolus as demarcated by fibrillarin (blue) in this fibroblast. (B) 4q35 (red, arrows) localizes within the peripheral rim (DAPI, blue) defined by depletion of hnRNA (green). (C) The peripheral localization of 4q (red) contrasts with the internal localization of 4p (green). Lamin A and nucleoli were detected simultaneously (blue). (D) The centromere of chromosome 4 (green) favors the nucleolus (blue), whereas the 4q telomere (red) is oriented at the periphery. (E) Analysis of three 4q subtelomeric probes reveals no preferred ordering between these three loci with respect to the periphery. RP11-279K24 (red) is more peripheral than RP11-597P9 (green) in one allele in contrast to the loci at the other allele. (F) Likewise, RP11-279K24 (red) is more peripheral than D4Z4 (green) in one allele in contrast to the other. (G) Chromosome 17q (red) and 17p (green) avoid the nuclear periphery and are often in the vicinity of the nucleolus (blue), particularly in myotubes. (H) The 17q (red) telomere frequently colocalizes with SC35 domains (blue) in a myoblast. (I) Quantitative distributions of total or specific telomeres (or centromere) in myoblasts. We analyzed 1,000 total telomeres, >800 4q, 200 4p, 200 4cen, 100 17p, and 100 17q signals.

Mentions: The distribution of the RP11-279 marker specific for 4q35.1 (the distal tip of chromosome 4q) was first examined in diploid human fibroblasts. Signals were deemed peripheral if within ∼0.6 μm from the nuclear edge as seen by DAPI and confirmed by nucleopore or lamin staining (see online supplemental material, available at http://www.jcb.org/cgi/content/full/jcb.200403128/DC1). As shown in Fig. 3 A, the 4q35 signal is located at the outer edge of the nuclear periphery and occasionally with the fibrillarin-stained nucleolus, where the D4Z4-bearing acrocentric chromosomes cluster (see Relationship of D4Z4 repeats on other chromosomes to the heterochromatic compartment). In fibroblasts, 73% of 4q35 signals associate with the heterochromatic compartment (65% nuclear and 8% nucleolar periphery). Given that FSHD is a muscular dystrophy, cultured human skeletal myoblasts and differentiated myotubes were examined, using procedures optimized for analysis of muscle nuclei (Smith et al., 1999). As shown in Fig. 3 (B and I), 87% of myoblast and 92% of myotube signals contacted either the nuclear or nucleolar periphery, with the vast majority (85% in muscle) at the nuclear periphery.


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)

The 4q telomere favors the heterochromatic compartment and, in particular, the nuclear periphery. This specific localization is striking when compared to other loci on chromosome 4 and to other telomeres. (A) The 4q35 (red, arrows) is found at either the nuclear periphery or next to the nucleolus as demarcated by fibrillarin (blue) in this fibroblast. (B) 4q35 (red, arrows) localizes within the peripheral rim (DAPI, blue) defined by depletion of hnRNA (green). (C) The peripheral localization of 4q (red) contrasts with the internal localization of 4p (green). Lamin A and nucleoli were detected simultaneously (blue). (D) The centromere of chromosome 4 (green) favors the nucleolus (blue), whereas the 4q telomere (red) is oriented at the periphery. (E) Analysis of three 4q subtelomeric probes reveals no preferred ordering between these three loci with respect to the periphery. RP11-279K24 (red) is more peripheral than RP11-597P9 (green) in one allele in contrast to the loci at the other allele. (F) Likewise, RP11-279K24 (red) is more peripheral than D4Z4 (green) in one allele in contrast to the other. (G) Chromosome 17q (red) and 17p (green) avoid the nuclear periphery and are often in the vicinity of the nucleolus (blue), particularly in myotubes. (H) The 17q (red) telomere frequently colocalizes with SC35 domains (blue) in a myoblast. (I) Quantitative distributions of total or specific telomeres (or centromere) in myoblasts. We analyzed 1,000 total telomeres, >800 4q, 200 4p, 200 4cen, 100 17p, and 100 17q signals.
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fig3: The 4q telomere favors the heterochromatic compartment and, in particular, the nuclear periphery. This specific localization is striking when compared to other loci on chromosome 4 and to other telomeres. (A) The 4q35 (red, arrows) is found at either the nuclear periphery or next to the nucleolus as demarcated by fibrillarin (blue) in this fibroblast. (B) 4q35 (red, arrows) localizes within the peripheral rim (DAPI, blue) defined by depletion of hnRNA (green). (C) The peripheral localization of 4q (red) contrasts with the internal localization of 4p (green). Lamin A and nucleoli were detected simultaneously (blue). (D) The centromere of chromosome 4 (green) favors the nucleolus (blue), whereas the 4q telomere (red) is oriented at the periphery. (E) Analysis of three 4q subtelomeric probes reveals no preferred ordering between these three loci with respect to the periphery. RP11-279K24 (red) is more peripheral than RP11-597P9 (green) in one allele in contrast to the loci at the other allele. (F) Likewise, RP11-279K24 (red) is more peripheral than D4Z4 (green) in one allele in contrast to the other. (G) Chromosome 17q (red) and 17p (green) avoid the nuclear periphery and are often in the vicinity of the nucleolus (blue), particularly in myotubes. (H) The 17q (red) telomere frequently colocalizes with SC35 domains (blue) in a myoblast. (I) Quantitative distributions of total or specific telomeres (or centromere) in myoblasts. We analyzed 1,000 total telomeres, >800 4q, 200 4p, 200 4cen, 100 17p, and 100 17q signals.
Mentions: The distribution of the RP11-279 marker specific for 4q35.1 (the distal tip of chromosome 4q) was first examined in diploid human fibroblasts. Signals were deemed peripheral if within ∼0.6 μm from the nuclear edge as seen by DAPI and confirmed by nucleopore or lamin staining (see online supplemental material, available at http://www.jcb.org/cgi/content/full/jcb.200403128/DC1). As shown in Fig. 3 A, the 4q35 signal is located at the outer edge of the nuclear periphery and occasionally with the fibrillarin-stained nucleolus, where the D4Z4-bearing acrocentric chromosomes cluster (see Relationship of D4Z4 repeats on other chromosomes to the heterochromatic compartment). In fibroblasts, 73% of 4q35 signals associate with the heterochromatic compartment (65% nuclear and 8% nucleolar periphery). Given that FSHD is a muscular dystrophy, cultured human skeletal myoblasts and differentiated myotubes were examined, using procedures optimized for analysis of muscle nuclei (Smith et al., 1999). As shown in Fig. 3 (B and I), 87% of myoblast and 92% of myotube signals contacted either the nuclear or nucleolar periphery, with the vast majority (85% in muscle) at the nuclear periphery.

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