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The ICF syndrome is a rare autosomal recessive disorder, the most common symptoms of which are immunodeficiency, facial anomalies and cytogenetic defects involving decondensation and instability of chromosome 1, 9 and 16 centromeric regions. ICF is also characterised by significant hypomethylation of the classical satellite DNA, the major constituent of the juxtacentromeric heterochromatin. Here we report the first attempt at analysing some of the defining genetic and epigenetic changes of this syndrome from a nuclear architecture perspective. In particular, we have compared in ICF (Type 1 and Type 2) and controls the large-scale organisation of chromosome 1 and 16 juxtacentromeric heterochromatic regions, their intra-nuclear positioning, and co-localisation with five specific genes (BTG2, CNN3, ID3, RGS1, F13A1), on which we have concurrently conducted expression and methylation analysis. Our investigations, carried out by a combination of molecular and cytological techniques, demonstrate the existence of specific and quantifiable differences in the genomic and nuclear organisation of the juxtacentromeric heterochromatin in ICF. DNA hypomethylation, previously reported to correlate with the decondensation of centromeric regions in metaphase described in these patients, appears also to correlate with the heterochromatin spatial configuration in interphase. Finally, our findings on the relative positioning of hypomethylated satellite sequences and abnormally expressed genes suggest a connection between disruption of long-range gene-heterochromatin associations and some of the changes in gene expression in ICF. Beyond its relevance to the ICF syndrome, by addressing fundamental principles of chromosome functional organisation within the cell nucleus, this work aims to contribute to the current debate on the epigenetic impact of nuclear architecture in development and disease. © 2010 Jefferson et al.

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