Chromosome territory re-organisation in a human disease with altered DNA methylation

Chromosome territory (CT) organisation and chromatin condensation have been linked to gene expression. Although individual genes can be transcribed from inside CTs, some regions of constitutively high expression, or that are coordinately activated, loop out from CTs and decondense. The relationship between epigenetic marks, such as DNA methylation, and higher-order chromatin structures is little explored. DNMT3B mutations in ICF (Immunodeficiency, Centromeric instability, Facial anomalies) syndrome result in loss of DNA methylation at particular sites, including CpG islands on Xi (inactive X). This allows the specific effects of DNA methylation on CTs to be examined. Using fluorescence in situ hybridisation, we reveal a differential organisation of the human PAR2 (Pseudoautosomal region 2) between the CTs of the X and Y in normal males, and the active X (Xa) and the Xi in females. There is also a more condensed chromatin structure on Xi compared to Xa in this region. PAR2 genes are relocalised towards the outside of the Y and Xi CTs in ICF and on the Xi we show that this can extend to genes distant from the site of DNA hypomethylation itself. This re-organisation is not simply a reflection of the transcriptional activation of the relocalised genes. This first report of altered CT organisation in a human genetic disease illustrates that DNA hypomethylation at restricted sites in the genome can lead to more extensive changes in nuclear organisation away from the original site of epigenetic change.