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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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Heterochromatin forms a compartment at the nuclear and nucleolar periphery in human fibroblasts and muscle cells. (A) Late-replicating DNA (labeled by BrdU; green) concentrates at the nuclear periphery, whereas SC35 domains rich in RNA metabolic factors (red) punctuate the nuclear interior. (B) Heterochromatin, primarily at the nuclear periphery and nucleolus, is delineated as the DAPI region (blue) devoid of hnRNA (red). Inset shows magnification of the periphery. The image was deconvolved to minimize out-of-focus light. (C) This myotube highlights the prominent peripheral heterochromatin compartment in five nuclei as described in B. (D) The inactive X chromosome marked by the accumulation of Xist RNA (green) is localized either at the nucleolus or at the nuclear periphery (E).
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fig1: Heterochromatin forms a compartment at the nuclear and nucleolar periphery in human fibroblasts and muscle cells. (A) Late-replicating DNA (labeled by BrdU; green) concentrates at the nuclear periphery, whereas SC35 domains rich in RNA metabolic factors (red) punctuate the nuclear interior. (B) Heterochromatin, primarily at the nuclear periphery and nucleolus, is delineated as the DAPI region (blue) devoid of hnRNA (red). Inset shows magnification of the periphery. The image was deconvolved to minimize out-of-focus light. (C) This myotube highlights the prominent peripheral heterochromatin compartment in five nuclei as described in B. (D) The inactive X chromosome marked by the accumulation of Xist RNA (green) is localized either at the nucleolus or at the nuclear periphery (E).

Mentions: In a preliminary analysis of the FSHD locus organization in lymphocytes, we noted a high percentage of 4q35 signals (45–50%) at the nuclear periphery; in contrast, a U2 snRNA locus probe showed <10% peripheral. Because the random rotation of lymphocytes in suspension complicates analysis and minimizes the apparent frequency of peripheral signals, we focused our work on primary human cells with a defined dorsal/ventral axis in culture. First, heterochromatic and euchromatic nuclear compartments were defined for human fibroblasts, myoblasts, and differentiated muscle. As shown in Fig. 1, late replicating heterochromatic DNA is concentrated around the nuclear periphery, whereas splicing factor (SC35) domains, associated with many active genomic regions (Shopland et al., 2003), are confined to the more internal euchromatic compartment (Fig. 1 A; Carter et al., 1993). These two compartments are also marked differentially by hnRNA, recently shown to distinguish the inactive from the active X chromosomes (Hall et al., 2002; see Materials and methods). The peripheral rim of the nucleus is consistently devoid of hnRNA in both fibroblasts (Fig. 1 B) and muscle (Fig. 1 C). A second region of heterochromatin abuts the nucleolus, consistent with ultrastructural observations (Comings, 1980) and corroborated by the localization of the heterochromatic inactive X to either the nuclear or the nucleolar periphery (Fig. 1, D and E). Thus, in our analysis we considered both the nuclear periphery adjacent to the lamina and the region abutting the nucleolus as common components of the heterochromatic compartment.


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)

Heterochromatin forms a compartment at the nuclear and nucleolar periphery in human fibroblasts and muscle cells. (A) Late-replicating DNA (labeled by BrdU; green) concentrates at the nuclear periphery, whereas SC35 domains rich in RNA metabolic factors (red) punctuate the nuclear interior. (B) Heterochromatin, primarily at the nuclear periphery and nucleolus, is delineated as the DAPI region (blue) devoid of hnRNA (red). Inset shows magnification of the periphery. The image was deconvolved to minimize out-of-focus light. (C) This myotube highlights the prominent peripheral heterochromatin compartment in five nuclei as described in B. (D) The inactive X chromosome marked by the accumulation of Xist RNA (green) is localized either at the nucleolus or at the nuclear periphery (E).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2172553&req=5

fig1: Heterochromatin forms a compartment at the nuclear and nucleolar periphery in human fibroblasts and muscle cells. (A) Late-replicating DNA (labeled by BrdU; green) concentrates at the nuclear periphery, whereas SC35 domains rich in RNA metabolic factors (red) punctuate the nuclear interior. (B) Heterochromatin, primarily at the nuclear periphery and nucleolus, is delineated as the DAPI region (blue) devoid of hnRNA (red). Inset shows magnification of the periphery. The image was deconvolved to minimize out-of-focus light. (C) This myotube highlights the prominent peripheral heterochromatin compartment in five nuclei as described in B. (D) The inactive X chromosome marked by the accumulation of Xist RNA (green) is localized either at the nucleolus or at the nuclear periphery (E).
Mentions: In a preliminary analysis of the FSHD locus organization in lymphocytes, we noted a high percentage of 4q35 signals (45–50%) at the nuclear periphery; in contrast, a U2 snRNA locus probe showed <10% peripheral. Because the random rotation of lymphocytes in suspension complicates analysis and minimizes the apparent frequency of peripheral signals, we focused our work on primary human cells with a defined dorsal/ventral axis in culture. First, heterochromatic and euchromatic nuclear compartments were defined for human fibroblasts, myoblasts, and differentiated muscle. As shown in Fig. 1, late replicating heterochromatic DNA is concentrated around the nuclear periphery, whereas splicing factor (SC35) domains, associated with many active genomic regions (Shopland et al., 2003), are confined to the more internal euchromatic compartment (Fig. 1 A; Carter et al., 1993). These two compartments are also marked differentially by hnRNA, recently shown to distinguish the inactive from the active X chromosomes (Hall et al., 2002; see Materials and methods). The peripheral rim of the nucleus is consistently devoid of hnRNA in both fibroblasts (Fig. 1 B) and muscle (Fig. 1 C). A second region of heterochromatin abuts the nucleolus, consistent with ultrastructural observations (Comings, 1980) and corroborated by the localization of the heterochromatic inactive X to either the nuclear or the nucleolar periphery (Fig. 1, D and E). Thus, in our analysis we considered both the nuclear periphery adjacent to the lamina and the region abutting the nucleolus as common components of the heterochromatic compartment.

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