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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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Subtelomeres containing D4Z4 repeats tend to localize to the heterochromatic compartment in both fibroblasts and muscle. (A) Ideogram depicting the known positions and rough size of D4Z4 (red) and β satellite repeats (green; Lyle et al., 1995; Lemmers et al., 2002). (B) Both 4q (red) and 10q (green) favor the nuclear or nucleolar periphery (blue) in fibroblasts. (C) 10q (green) near the nuclear or nucleolar periphery (blue) in myoblasts. (D) A maximal intensity projection showing all D4Z4 signals (green) in a three-dimensional stack in muscle (red, 4q). D4Z4 telomeres cluster at the nucleolus (blue, arrow). (E) Quantitative summary showing that the distribution of the D4Z4 subtelomere family is a distinctive subset from that of total telomeres (in myoblasts). We analyzed >800 4q, 100 10q, 100 D4Z4, and 1,000 total telomere signals.
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fig7: Subtelomeres containing D4Z4 repeats tend to localize to the heterochromatic compartment in both fibroblasts and muscle. (A) Ideogram depicting the known positions and rough size of D4Z4 (red) and β satellite repeats (green; Lyle et al., 1995; Lemmers et al., 2002). (B) Both 4q (red) and 10q (green) favor the nuclear or nucleolar periphery (blue) in fibroblasts. (C) 10q (green) near the nuclear or nucleolar periphery (blue) in myoblasts. (D) A maximal intensity projection showing all D4Z4 signals (green) in a three-dimensional stack in muscle (red, 4q). D4Z4 telomeres cluster at the nucleolus (blue, arrow). (E) Quantitative summary showing that the distribution of the D4Z4 subtelomere family is a distinctive subset from that of total telomeres (in myoblasts). We analyzed >800 4q, 100 10q, 100 D4Z4, and 1,000 total telomere signals.

Mentions: The aforementioned results demonstrate that a full complement of D4Z4 repeats is not required for the nuclear localization of 4q35 to the heterochromatic compartment. However, if D4Z4 repeats have some functional relationship to heterochromatin and/or nuclear compartmentalization, other chromosomal loci bearing these repeats may show commonalities in their interphase organization with the nuclear or nucleolar periphery. As depicted in Fig. 7 A, D4Z4 repeats are detected in the subtelomeres of the five acrocentric chromosomes as well as 4q, 10q, and 1q12 (Lyle et al., 1995; Winokur et al., 1996), indicating that D4Z4 comprises a specific family of subtelomeric repeats with unknown function.


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)

Subtelomeres containing D4Z4 repeats tend to localize to the heterochromatic compartment in both fibroblasts and muscle. (A) Ideogram depicting the known positions and rough size of D4Z4 (red) and β satellite repeats (green; Lyle et al., 1995; Lemmers et al., 2002). (B) Both 4q (red) and 10q (green) favor the nuclear or nucleolar periphery (blue) in fibroblasts. (C) 10q (green) near the nuclear or nucleolar periphery (blue) in myoblasts. (D) A maximal intensity projection showing all D4Z4 signals (green) in a three-dimensional stack in muscle (red, 4q). D4Z4 telomeres cluster at the nucleolus (blue, arrow). (E) Quantitative summary showing that the distribution of the D4Z4 subtelomere family is a distinctive subset from that of total telomeres (in myoblasts). We analyzed >800 4q, 100 10q, 100 D4Z4, and 1,000 total telomere signals.
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Related In: Results  -  Collection

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fig7: Subtelomeres containing D4Z4 repeats tend to localize to the heterochromatic compartment in both fibroblasts and muscle. (A) Ideogram depicting the known positions and rough size of D4Z4 (red) and β satellite repeats (green; Lyle et al., 1995; Lemmers et al., 2002). (B) Both 4q (red) and 10q (green) favor the nuclear or nucleolar periphery (blue) in fibroblasts. (C) 10q (green) near the nuclear or nucleolar periphery (blue) in myoblasts. (D) A maximal intensity projection showing all D4Z4 signals (green) in a three-dimensional stack in muscle (red, 4q). D4Z4 telomeres cluster at the nucleolus (blue, arrow). (E) Quantitative summary showing that the distribution of the D4Z4 subtelomere family is a distinctive subset from that of total telomeres (in myoblasts). We analyzed >800 4q, 100 10q, 100 D4Z4, and 1,000 total telomere signals.
Mentions: The aforementioned results demonstrate that a full complement of D4Z4 repeats is not required for the nuclear localization of 4q35 to the heterochromatic compartment. However, if D4Z4 repeats have some functional relationship to heterochromatin and/or nuclear compartmentalization, other chromosomal loci bearing these repeats may show commonalities in their interphase organization with the nuclear or nucleolar periphery. As depicted in Fig. 7 A, D4Z4 repeats are detected in the subtelomeres of the five acrocentric chromosomes as well as 4q, 10q, and 1q12 (Lyle et al., 1995; Winokur et al., 1996), indicating that D4Z4 comprises a specific family of subtelomeric repeats with unknown function.

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