Gene re-localization in nuclei upon activation is a well documented finding although how general this phenomenon is remains in question [27
]. In animal cells, the migration typically involves moving from a peripheral position to a more interior one. Thus, the β-globin locus moves away from the nuclear periphery in maturing fetal liver cell nuclei before becoming highly. Re-localization requires the β-globin LCR but also the protein factor Ldb1, required for looping [30
]. Recent work shows that GATA-1, its co-factor FOG1, EKLF (KLF1
) and chromatin remodeler Mi-2β are also required for migration of the β-globin locus to the nuclear interior [32
]. Locus movement occurred before the appearance of key markers of erythroid differentiation, suggesting it is a pre-requisite and not a consequence of high level transcription. Interestingly, inactivation of FOG-1 and Μi-2β after re-localization did not return β-globin loci to the nuclear periphery [32
Very recently it has been shown that the Eµ enhancer is required for movement of the IgH locus to the nuclear interior [33
]. Enhancer dependent long range interactions involved YY1 binding to Eµ and to the sites with which it interacted. Taken together, these results implicate enhancers and factors required for enhancer loops to form in locus movement, raising the question whether looping precedes locus migration. The Eµ enhancer loops and IgH locus migration occur without recombination or transcription of the rearranged gene, arguing that looping and migration happen first (). Alternatively, looping might occur after association with a transcription factory, possibly as a result of transcription (). Further experiments will be necessary to distinguish these models and illuminate this fundamental question.
Influence of enhancer-promoter interaction on intra-nuclear migration to a transcription factory
Intra-nuclear migration during transcription activation correlates with entry into a transcription factory [34
]. These entities are independent nuclear sub-compartments that are repositories of hyper-phosphorylated RNA pol II [35
]. The β-globin locus enters a transcription factory after migration away from the nuclear periphery [30
]. If transcription is interrupted the LCR- β-globin loop is retained, arguing that at least the maintenance of this proximity does not require ongoing transcription or even residence in a transcription factory [35
]. Furthermore, the choice of transcription factory is non-random [37
]. EKLF-dependent genes, including β-globin, co-localize at a subset of “specialized” factories that are enriched for EKLF. The underlying mechanisms are unclear. Do EKLF regulated genes seek out the proper factory, or are genes regulated by EKLF first bound by the factor and then co-migrate to a factory making it “specialized”. The precise sequence of events and interrelationships among factor binding, enhancer looping and intra-nuclear migration remain to be established.