A genetic analysis of chromosome territory looping: Diverse roles for distal regulatory elements

Recent studies of nuclear organization have shown an apparent correlation between the localization of genes within the interphase nucleus and their transcriptional status. In several instances, actively transcribed gene loci have been found significantly looped away from their respective chromosome territories (CTs), presumably as a result of their expression. Here, we show evidence that extrusion of a gene locus from a CT by itself is not necessarily indicative of transcriptional activity, but also can reflect a poised state for activation. We found the murine and a wild-type human β-globin locus looped away from their CTs at a high frequency only in a proerythroblast cell background, prior to the activation of globin transcription. Conversely, a mutant allele lacking the locus control region (LCR), which is required for high-level globin expression, was mostly coincident with the CT. The LCR may thus be responsible for the localization of the globin locus prior to activation. Replacement of the LCR with a B-cell-specific regulatory element, while also extruding the globin locus, brought it closer to the repressive centromeric heterochromatin compartment. We therefore suggest that the looping of gene loci from their CTs may reflect poised and repressed states, as well as the previously documented transcriptionally active state.