Movement of the X Chromosome in Epilepsy

Abstract

The position of selected chromosomes was assessed in samples of normal and epileptic human cortex with biotinylated probes specific for individual chromosome domains. Optical sectioning provided a rapid method for three-dimensional resolution of in situ hybridization signals in interphase cells, and solid models were reconstructed from digitized images for detailed rotational studies. There was a dramatic repositioning of the X chromosome in neurons of both males and females in electrophysiologically defined seizure foci. Other chromosomes (1, 9, and Y) showed more subtle positional changes. Specifically altered nuclear patterns involving the X chromosome may become established and create the genetic memory for intractable seizure activity.

Loss of neuronal 3D chromatin organization causes transcriptional and behavioural deficits related to serotonergic dysfunction

“…Furthermore, recent studies have shown that gene mutations associated with intellectual disability in humans affect chromatin compactation and the number and size of chromocenters in cortical neurons 15,16 . The reported changes in the spatial distribution of satellite DNA and active loci in hippocampal neurons after seizures or experimentally induced long-term potentiation also support a role for higher-order chromatin structures in neuronal function [17][18][19] . Also consistent with this view, a recent study has revealed chromosomal conformation changes in the chromatin of the prefrontal cortex of schizophrenic patients that specifically affected the GAD1 locus 20 .…”

Disease-specific gene repositioning in breast cancer

“…Importantly, large-scale alterations of spatial organization also occur in pathological states (Borden and Manuelidis, 1988;Zink et al, 2004;Meaburn et al, 2007). A major hallmark of many cancers, which is routinely exploited by pathologists, is the distinctive changes to cancer nuclei at the gross level, such as to nuclear shape and chromatin texture (Zink et al, 2004).…”

Spatial genome organization in the formation of chromosomal translocations

“…In addition to tissue specific genome organisation, changes in the spatial organisation of the genome have been observed in several diseases, including cancer [10,25,[33][34][35][36], epilepsy [37], and laminopathies, a group of diseases caused by mutation in the nuclear proteins lamin A/C [16], further suggesting a link between positioning and genome activity rather than simply gene density.…”