3D-FISH analysis reveals chromatid cohesion defect during interphase in Roberts syndrome

Molecular Cytogenetics

Jean-Michel Dupont⁶  Brigitte Benzacken⁵  Anne-Claude Tabet³  Pierre Bourdoncle⁸  Emmanuel Spaggiari¹  Benedicte Gerard²  Camille Lebugle⁸  Dominique Le Tessier⁶  Daniel Smiljkovski⁶  Lilia Kraoua²  Fabien Guimiot⁴  Martine Bucourt⁷  Celine Dupont³ 

[1] Service de Biologie du Développement- APHP, Hôpital Robert Debré, Paris, France;Unité fonctionnelle de Génétique moléculaire - Département de Génétique- APHP, Hôpital Robert Debré, Paris, France;Unité fonctionnelle de Cytogénétique-Département de Génétique- APHP, Hôpital Robert Debré, 48 Bd Sérurier, Paris, 75935, France;Université Paris Diderot Sorbonne Paris Cité, UMR 1141, Paris, F-75019, France;Service d¿Histologie, Embryologie et Cytogénétique, Biologie de la Reproduction- APHP, Hôpital Jean Verdier, Bondy, France; UFR-SMBH, Paris XIII, France;Laboratoire de Cytogénétique- APHP, Hôpitaux Universitaires Paris Centre, Paris, France;Laboratoire de F¿topathologie- APHP, Hôpital Jean Verdier, Bondy, France;Institut Cochin, Plateforme d¿imagerie cellulaire, Paris, France

关键词: Limb development;    Heterochromatin;    ESCO2;    Cohesinopathy;   

Others  :  1149763
DOI  :  10.1186/s13039-014-0059-6

 received in 2014-06-11, accepted in 2014-08-21,  发布年份 2014

【 摘 要 】

Background

Roberts syndrome (RBS) is a rare autosomal recessive disorder mainly characterized by growth retardation, limb defects and craniofacial anomalies. Characteristic cytogenetic findings are ¿railroad track¿ appearance of chromatids and premature centromere separation in metaphase spreads. Mutations in the ESCO2 (establishment of cohesion 1 homolog 2) gene located in 8p21.1 have been found in several families. ESCO2, a member of the cohesion establishing complex, has a role in the effective cohesion between sister chromatids. In order to analyze sister chromatids topography during interphase, we performed 3D-FISH using pericentromeric heterochromatin probes of chromosomes 1, 4, 9 and 16, on preserved nuclei from a fetus with RBS carrying compound heterozygous null mutations in the ESCO2 gene.

Results

Along with the first observation of an abnormal separation between sister chromatids in heterochromatic regions, we observed a statistically significant change in the intranuclear localization of pericentromeric heterochromatin of chromosome 1 in cells of the fetus compared to normal cells, demonstrating for the first time a modification in the spatial arrangement of chromosome domains during interphase.

Conclusion

We hypothesize that the disorganization of nuclear architecture may result in multiple gene deregulations, either through disruption of DNA cis interaction ¿such as modification of chromatin loop formation and gene insulation - mediated by cohesin complex, or by relocation of chromosome territories. These changes may modify interactions between the chromatin and the proteins associated with the inner nuclear membrane or the pore complexes. This model offers a link between the molecular defect in cohesion and the complex phenotypic anomalies observed in RBS.

【 授权许可】

   
2014 Dupont et al.; licensee BioMed Central Ltd.

【 图 表 】

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