Enhancer and promoter interactions-long distance calls

Abstract

In metazoans, enhancers of gene transcription must often exert their effects over tens of kilobases of DNA. Over the past decade it has become clear that to do this, enhancers come into close proximity with target promoters with the looping away of intervening sequences. In a few cases proteins that are involved in the establishment or maintenance of these loops have been revealed but how the proper gene target is selected remains mysterious. Chromatin insulators had been appreciated as elements that play a role in enhancer fidelity through their enhancer blocking or barrier activity. However, recent work suggests more direct participation of insulators in enhancer-gene interactions. The emerging view begins to incorporate transcription activation by distant enhancers with large scale nuclear architecture and subnuclear movement.

Figure 1. Models of enhancer and insulator function

A. An enhancer is depicted as activating transcription from a target gene promoter through direct interaction over a large distance by creating a chromatin loop. B. An insulator located between an enhancer and a gene can block promoter-enhancer interaction by acting as a road block to a processive signal from the enhancer or by forming a loop with another insulator located distal to the gene. C. An insulator functions as a barrier to block the spreading of repressive chromatin into an inappropriate locus. This function is depicted as a road block but could also be carried out as in panel 1B by the insulator interacting directly with another insulator to form a loop encompassing the active gene. In all panels, the yellow rectangle is the enhancer and the blue rectangle is the gene. The red rectangle is the insulator. The hatched rectangle represents condensed heterochromatin.

Figure 2. Influence of enhancer-promoter interaction on intra-nuclear migration to a transcription factory

Before activation a locus occupies a position near the nuclear periphery and the enhancer and promoter do not yet interact with each other. A. In one view, after activation the enhancer interacts with the promoter which in turn leads to locus migration into the nuclear interior and localization in an RNA pol II transcription factory. Subsequently, transcription at the enhancer and promoter produces ncRNA that stabilize the interaction and mRNA respectively. B. Alternatively, the locus migrates to an interior position without communication between the enhancer and the target gene promoter and their interaction is established in the RNA polII factory, possibly with the participation of the ncRNA transcript. Designations are the same as in Figure 1.

Figure 3. CTCF role in facilitating long range interaction between an enhancer and promoter

A. CTCF mediates interaction between two insulators which positively influences enhancer-promoter interaction. This model reflects the arrangement in the β-globin and APO loci [4;48]. B. CTCF interacts with an enhancer and target promoter and participates directly in long range interaction between them that leads to transcription activation. Examples of this arrangement have been recently been described [49]. C. CTCF interacts with an insulator and provides interaction with a promoter which in turn activates transcription. The INFG and MHC class II loci provide examples of this mechanism [51;53]. D. Insulator bound CTCF provides interaction with an enhancer which in turn interacts with a target promoter. This mechanism is utilized in the IgH locus [54;55]. Variants A, C and D can be incorporated into the concept of the active chromatin hub which provides an environment conducive to transcription activation. Designations are as in Figure 1.