Nuclear Organization

As is the case with other genes, nuclear compartmentalization and organization appears to impact p-globin gene regulation. Both the human locus on chromosome 11 and the mouse locus on chromosome 7 reside in regions of high gene density. Bickmore and colleagues have demonstrated a correlation between the gene density of regions in which a particular gene resides and its nuclear position relative to the chromosomal territory (Mahy et al. 2002b). They found that genes on human chromosome 11 and mouse chromosome 7, in the gene-rich region containing the globin genes, tend to be located on the edge of the territory, or indeed outside the territory, presumably looped out from the intensely stained territorial mass. In contrast, genes located in relatively gene-poor regions tend to reside within the bulk of the territory. Although transcription may be able to occur within the central regions of the territory, extraterritorial positioning appears also to relate to transcriptional status or potential (Mahy et al. 2002a). Treatment of cells with transcriptional inhibitors results in movement of extraterritorial regions to more territory-proximal positions. Whereas the p-globin locus has been observed in a slightly internal position relative to the chromosome territory and adjacent to centromeric heterochromatin in lymphoid cells (Brown et al. 2001), it is often in an extraterritorial position in MEL cells (Ragoczy et al. 2003).

The LCR is likely to contribute to functional positioning of the p-globin locus. The human locus does not adopt an extraterritorial position in MEL cell hybrids when the LCR has been deleted from chromosome 11 (Ragoczy et al. 2003). Furthermore, the Hispanic thalassaemia deletion, which removes the LCR and approximately 30 kb of upstream sequences including the LTR, causes the locus to locate to centromeric heterochromatin (Schubeler et al. 2000), whereas loci with deletions that remove only parts of the LCR remain positioned away from centromeric heterochromatin. This suggests that positioning away from repressive chromatin environments may be linked to sequences outside the LCR.

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