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Enhancers and silencers: an integrated and simple model for their function - PubMed

  • ️Sun Jan 01 2012

Enhancers and silencers: an integrated and simple model for their function

Petros Kolovos et al. Epigenetics Chromatin. 2012.

Abstract

Regulatory DNA elements such as enhancers, silencers and insulators are embedded in metazoan genomes, and they control gene expression during development. Although they fulfil different roles, they share specific properties. Herein we discuss some examples and a parsimonious model for their function is proposed. All are transcription units that tether their target promoters close to, or distant from, transcriptional hot spots (or 'factories').

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Figures

Figure 1
Figure 1

Existing models for the function of enhancers. The four existing models describing gene regulation by enhancers are depicted. (A) The tracking model, where a transcription factor (purple hexagon) loads onto the enhancer and tracks along the chromatin fibre towards the promoter, where it stimulates transcription by association with the polymerase (pink oval). (B) The linking model, where the loaded transcription factor drives polymerization of proteins in the direction of the promoter. (C) The relocation model, where a gene relocates to nuclear subcompartments (pink halo) favouring enhancer-promoter interactions, and so transcription. (D) The looping model, where the enhancer comes into proximity with the relevant promoter due to protein-protein interactions. This loops out the intervening chromatin and triggers transcriptional activation.

Figure 2
Figure 2

A simple model for the function of regulatory elements. Spheres A, B and C represent factories rich in different sets of transcription factors and associated halos indicate the probability that promoter 1, 2 or 3 will collide with a factory (red indicates high probability). The low-probability zone immediately around the factory arises because the intrinsic stiffness of the chromatin fibre restricts the formation of very small loops). Curved black arrow indicates collision between promoter and factory that yields a productive initiation. Dashed grey arrows indicate the preferred site of initiation (as factory B is rich in the relevant transcription factors). Blocked red arrows indicate unproductive collisions (as the factory contains few of the relevant factors). (A) Enhancers and silencers. Transcription unit 1 is being transcribed by a polymerase in factory A. This tethers unit 2 in a 'hot zone', where it has a high probability of colliding with a polymerase in factory A (which contains high local concentrations of factors necessary for initiation by promoters 1 and 2). As a result, unit 1 acts as an enhancer for unit 2. At the same time, unit 3 is tethered far from factory B (which is rich in the factors required for its initiation). Here unit 1 acts as a silencer of unit 3. (B) Insulator. At a different stage in development, a different constellation of transcription factors are expressed. Chromatin domains containing units 2 and 3 are separated by unit 1 (now transcribed in factory C, which contains low concentrations of the factors required by units 2 and 3), so they rarely bind to factory A and interact. Here unit 1 acts as an insulator or barrier.

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