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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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Positioning of 4q35 at the nuclear periphery resists perturbation. (A) Human 4q35 locus (green) in the foreign nucleoplasm of a mouse somatic cell hybrid. AT-rich mouse chromocenters (centromeres) are apparent by DAPI (blue). (B) The nuclear and nucleolar periphery are favored over mouse chromocenters as preferred sites for 4q35 localization (100 cells analyzed). (C) Quantitation of nuclear positions of translocated loci 4q35 and Xp21 (analysis of 150 cells per sample). As discussed by Kosak et al. (2002), 50% peripheral by two-dimensional analysis in freely rotated suspension cells corresponds to ∼95% peripheral localization in three-dimensional analysis. (D) Ideogram of the normal and the derivative chromosomes with the relative positions of the probes used in this work. (E) Normal female lymphocyte line and translocation cell line (F) with Xp21 marking the X chromosomes (red) and Xist RNA (green) identifying the inactive X. (G) Translocation cell line with Xp21 (red) on both X chromosomes and a 4q35 marker (green) identifying the derivative X. (H and I) Translocation cell line with 4q35 (green) on both chromosome 4s and D4Z4 (red) identifying the normal 4.
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fig6: Positioning of 4q35 at the nuclear periphery resists perturbation. (A) Human 4q35 locus (green) in the foreign nucleoplasm of a mouse somatic cell hybrid. AT-rich mouse chromocenters (centromeres) are apparent by DAPI (blue). (B) The nuclear and nucleolar periphery are favored over mouse chromocenters as preferred sites for 4q35 localization (100 cells analyzed). (C) Quantitation of nuclear positions of translocated loci 4q35 and Xp21 (analysis of 150 cells per sample). As discussed by Kosak et al. (2002), 50% peripheral by two-dimensional analysis in freely rotated suspension cells corresponds to ∼95% peripheral localization in three-dimensional analysis. (D) Ideogram of the normal and the derivative chromosomes with the relative positions of the probes used in this work. (E) Normal female lymphocyte line and translocation cell line (F) with Xp21 marking the X chromosomes (red) and Xist RNA (green) identifying the inactive X. (G) Translocation cell line with Xp21 (red) on both X chromosomes and a 4q35 marker (green) identifying the derivative X. (H and I) Translocation cell line with 4q35 (green) on both chromosome 4s and D4Z4 (red) identifying the normal 4.

Mentions: We explored a fundamental question concerning the nature of the 4q35 localization: a full complement of D4Z4 repeats is not required for peripheral positioning, but is this positioning an inherent property of this telomere? Is this chromosomal region specifically “tethered” or confined indirectly by other constraints of nuclear organization? We investigated this in two ways. First, we determined whether or not 4q35 was similarly oriented in a mouse–human somatic cell hybrid line, carrying a full complement of mouse chromosomes but only human chromosome 4. As shown in Fig. 6 (A and B), even in this foreign environment, 4q35 remains predominantly peripheral (68–73%) and moderately nucleolar (19%); thus, close to ∼90% were with the heterochromatic compartment. Interestingly, 4q35 shows no preferential association with the chromocenters (Fig. 6 B), easily detectable in mouse due to the affinity of their AT-rich centromeres for DAPI (Fig. 6 A). These results indicate that information within 4q alone is likely sufficient for nuclear partitioning of 4q35.


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)

Positioning of 4q35 at the nuclear periphery resists perturbation. (A) Human 4q35 locus (green) in the foreign nucleoplasm of a mouse somatic cell hybrid. AT-rich mouse chromocenters (centromeres) are apparent by DAPI (blue). (B) The nuclear and nucleolar periphery are favored over mouse chromocenters as preferred sites for 4q35 localization (100 cells analyzed). (C) Quantitation of nuclear positions of translocated loci 4q35 and Xp21 (analysis of 150 cells per sample). As discussed by Kosak et al. (2002), 50% peripheral by two-dimensional analysis in freely rotated suspension cells corresponds to ∼95% peripheral localization in three-dimensional analysis. (D) Ideogram of the normal and the derivative chromosomes with the relative positions of the probes used in this work. (E) Normal female lymphocyte line and translocation cell line (F) with Xp21 marking the X chromosomes (red) and Xist RNA (green) identifying the inactive X. (G) Translocation cell line with Xp21 (red) on both X chromosomes and a 4q35 marker (green) identifying the derivative X. (H and I) Translocation cell line with 4q35 (green) on both chromosome 4s and D4Z4 (red) identifying the normal 4.
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Related In: Results  -  Collection

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

fig6: Positioning of 4q35 at the nuclear periphery resists perturbation. (A) Human 4q35 locus (green) in the foreign nucleoplasm of a mouse somatic cell hybrid. AT-rich mouse chromocenters (centromeres) are apparent by DAPI (blue). (B) The nuclear and nucleolar periphery are favored over mouse chromocenters as preferred sites for 4q35 localization (100 cells analyzed). (C) Quantitation of nuclear positions of translocated loci 4q35 and Xp21 (analysis of 150 cells per sample). As discussed by Kosak et al. (2002), 50% peripheral by two-dimensional analysis in freely rotated suspension cells corresponds to ∼95% peripheral localization in three-dimensional analysis. (D) Ideogram of the normal and the derivative chromosomes with the relative positions of the probes used in this work. (E) Normal female lymphocyte line and translocation cell line (F) with Xp21 marking the X chromosomes (red) and Xist RNA (green) identifying the inactive X. (G) Translocation cell line with Xp21 (red) on both X chromosomes and a 4q35 marker (green) identifying the derivative X. (H and I) Translocation cell line with 4q35 (green) on both chromosome 4s and D4Z4 (red) identifying the normal 4.
Mentions: We explored a fundamental question concerning the nature of the 4q35 localization: a full complement of D4Z4 repeats is not required for peripheral positioning, but is this positioning an inherent property of this telomere? Is this chromosomal region specifically “tethered” or confined indirectly by other constraints of nuclear organization? We investigated this in two ways. First, we determined whether or not 4q35 was similarly oriented in a mouse–human somatic cell hybrid line, carrying a full complement of mouse chromosomes but only human chromosome 4. As shown in Fig. 6 (A and B), even in this foreign environment, 4q35 remains predominantly peripheral (68–73%) and moderately nucleolar (19%); thus, close to ∼90% were with the heterochromatic compartment. Interestingly, 4q35 shows no preferential association with the chromocenters (Fig. 6 B), easily detectable in mouse due to the affinity of their AT-rich centromeres for DAPI (Fig. 6 A). These results indicate that information within 4q alone is likely sufficient for nuclear partitioning of 4q35.

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