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A functional role for 4qA/B in the structural rearrangement of the 4q35 region and in the regulation of FRG1 and ANT1 in facioscapulohumeral dystrophy.

Pirozhkova I, Petrov A, Dmitriev P, Laoudj D, Lipinski M, Vassetzky Y - PLoS ONE (2008)

Bottom Line: The number of D4Z4 repeats in the subtelomeric region of chromosome 4q is strongly reduced in patients with Facio-Scapulo-Humeral Dystrophy (FSHD).We performed chromosome conformation capture (3C) analysis to document the interactions taking place among different 4q35 markers.We found that the reduced number of D4Z4 repeats in FSHD myoblasts was associated with a global alteration of the three-dimensional structure of the 4q35 region.

View Article: PubMed Central - PubMed

Affiliation: Université Paris-Sud 11, CNRS UMR 8126, Interactions moléculaires et cancer, Institut de Cancérologie Gustave-Roussy, Villejuif, France.

ABSTRACT
The number of D4Z4 repeats in the subtelomeric region of chromosome 4q is strongly reduced in patients with Facio-Scapulo-Humeral Dystrophy (FSHD). We performed chromosome conformation capture (3C) analysis to document the interactions taking place among different 4q35 markers. We found that the reduced number of D4Z4 repeats in FSHD myoblasts was associated with a global alteration of the three-dimensional structure of the 4q35 region. Indeed, differently from normal myoblasts, the 4qA/B marker interacted directly with the promoters of the FRG1 and ANT1 genes in FSHD cells. Along with the presence of a newly identified transcriptional enhancer within the 4qA allele, our demonstration of an interaction occurring between chromosomal segments located megabases away on the same chromosome 4q allows to revisit the possible mechanisms leading to FSHD.

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A–B. Models schematizing the proximity between 4q subtelomeric fragments in control (A) and FSHD (B) nuclei.
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pone-0003389-g004: A–B. Models schematizing the proximity between 4q subtelomeric fragments in control (A) and FSHD (B) nuclei.

Mentions: The experimental approach used here provides new ways to systematically explore the higher-order chromatin structure of any chromosomal region. In this study, we have found that the binding of DUX4c to the FRG1 and FRG2 gene promoters appears to play a key role in structuring the 4q35 region in normal cells. Other interactions take place in FSHD cells and this is the likely result of a global reorganization of the locus in relation with the contraction of the number of D4Z4 tandem repeats. This reorganization is schematized in the three dimensional model shown in Figure 4. In FSHD cells (Figure 4B), the deletion of D4Z4 repeats and the delocalization of the proximal S/MAR would result in the formation of a giant loop where the subtelomeric 4qA/B sequence is now brought in close proximity not only to DUX4C and FRG1 but also to the proximal ANT1 gene promoter which lies 5 Mbp away on the centromeric side of the region. This major structural rearrangement, as compared to the normal situation (Figure 4A), would make gene promoters accessible to the DUX4c and 4qA enhancers specifically in FSHD myoblasts. One hypothesis to explain how such long-range changes in higher order chromatin structure can occur relates to differences in the methylation status of the corresponding regions [27], [28]. Further studies are clearly needed to explore this and other hypotheses.


A functional role for 4qA/B in the structural rearrangement of the 4q35 region and in the regulation of FRG1 and ANT1 in facioscapulohumeral dystrophy.

Pirozhkova I, Petrov A, Dmitriev P, Laoudj D, Lipinski M, Vassetzky Y - PLoS ONE (2008)

A–B. Models schematizing the proximity between 4q subtelomeric fragments in control (A) and FSHD (B) nuclei.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2561064&req=5

pone-0003389-g004: A–B. Models schematizing the proximity between 4q subtelomeric fragments in control (A) and FSHD (B) nuclei.
Mentions: The experimental approach used here provides new ways to systematically explore the higher-order chromatin structure of any chromosomal region. In this study, we have found that the binding of DUX4c to the FRG1 and FRG2 gene promoters appears to play a key role in structuring the 4q35 region in normal cells. Other interactions take place in FSHD cells and this is the likely result of a global reorganization of the locus in relation with the contraction of the number of D4Z4 tandem repeats. This reorganization is schematized in the three dimensional model shown in Figure 4. In FSHD cells (Figure 4B), the deletion of D4Z4 repeats and the delocalization of the proximal S/MAR would result in the formation of a giant loop where the subtelomeric 4qA/B sequence is now brought in close proximity not only to DUX4C and FRG1 but also to the proximal ANT1 gene promoter which lies 5 Mbp away on the centromeric side of the region. This major structural rearrangement, as compared to the normal situation (Figure 4A), would make gene promoters accessible to the DUX4c and 4qA enhancers specifically in FSHD myoblasts. One hypothesis to explain how such long-range changes in higher order chromatin structure can occur relates to differences in the methylation status of the corresponding regions [27], [28]. Further studies are clearly needed to explore this and other hypotheses.

Bottom Line: The number of D4Z4 repeats in the subtelomeric region of chromosome 4q is strongly reduced in patients with Facio-Scapulo-Humeral Dystrophy (FSHD).We performed chromosome conformation capture (3C) analysis to document the interactions taking place among different 4q35 markers.We found that the reduced number of D4Z4 repeats in FSHD myoblasts was associated with a global alteration of the three-dimensional structure of the 4q35 region.

View Article: PubMed Central - PubMed

Affiliation: Université Paris-Sud 11, CNRS UMR 8126, Interactions moléculaires et cancer, Institut de Cancérologie Gustave-Roussy, Villejuif, France.

ABSTRACT
The number of D4Z4 repeats in the subtelomeric region of chromosome 4q is strongly reduced in patients with Facio-Scapulo-Humeral Dystrophy (FSHD). We performed chromosome conformation capture (3C) analysis to document the interactions taking place among different 4q35 markers. We found that the reduced number of D4Z4 repeats in FSHD myoblasts was associated with a global alteration of the three-dimensional structure of the 4q35 region. Indeed, differently from normal myoblasts, the 4qA/B marker interacted directly with the promoters of the FRG1 and ANT1 genes in FSHD cells. Along with the presence of a newly identified transcriptional enhancer within the 4qA allele, our demonstration of an interaction occurring between chromosomal segments located megabases away on the same chromosome 4q allows to revisit the possible mechanisms leading to FSHD.

Show MeSH
Related in: MedlinePlus