Stalled Hox promoters as chromosom ... | Article | H1 Connect

This interesting paper demonstrates that intrinsic properties of promoters contribute to the establishment of large domains of transcriptional fidelity. The long distance effects of enhancers and silencers, coupled with a limited specificity for promoter interactions, have indicated that eukaryotic genomes require insulators to constrain the actions of enhancers and silencers. Insulators block transcriptional effects of enhancers and silencers only when inserted between these control elements and target promoters. Over the years, two general models of insulator function have been proposed {please see ref 1, on which I am the author, and ref 2}. Structural models suggest insulators are architectural elements of genomes that organize loop domains that interfere with enhancer and silencer actions. Transcriptional models predict that insulators are transcriptional elements, derived from promoter regions, that decoy or mimic the target promoter, thereby disrupting the enhancer and silencer signaling to the target promoter. The Drosophila genome has the largest number of insulators, with recent genome-wide mapping studies providing a strong link between promoters and insulators {3-6}. Studies by Chopra et al. extend these mapping experiments through the demonstration that promoters that carry paused polymerases have the intrinsic ability to function as an insulator. These investigators noted that, in Hox gene clusters, all four genes at the boundaries of two clusters carry promoters with stalled polymerases. They demonstrate that Hox gene promoters with stalled polymerases block enhancer-activated transcription, in a position-dependent manner, without showing tethering activity. Intriguingly, these investigators show that NELF (negative elongation factor) is required for insulator effects of the Hox gene promoters, implying that production of a paused polymerase is required for this intrinsic insulator activity. These properties defined for the Hox promoters are likely to extend to many promoters genome-wide, as the insulator protein BEAF predominantly localizes to promoters and is commonly found associated with NELF {4}. Together, these data provide a strong support for transcriptional models of insulator function.

This interesting paper argues that paused RNA polymerase II (Pol II) can function as an insulator element, suggesting paused promoters may have active functions (organization of cis-regulatory architecture) and not merely passive ones (waiting for a trigger to activate Pol II elongation). The authors use standard insulator assays in Drosophila to show that regions with stalled Pol II behave like insulator elements and, conversely, that insulator elements require factors known to promote Pol II pausing. Relief of pausing by removal of negative elongation factors negates insulator activity. The authors note that stalled polymerase is seen for genes at the edge of Hox clusters, and suggest that the insulator activities may be particularly important at edges to buffer Hox genes from spurious regulation by elements outside of the Hox cluster.