Molecular Cell
Volume 76, Issue 3, 7 November 2019, Pages 473-484.e7
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Article
Decreased Enhancer-Promoter Proximity Accompanying Enhancer Activation

https://doi.org/10.1016/j.molcel.2019.07.038Get rights and content
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Highlights

  • Super-resolution microscopy reveals increased enhancer-promoter separation upon activation

  • Synthetic enhancer activation supports decreased enhancer-promoter proximity

  • Enhancer-promoter separation can be driven by poly(ADP-ribose) polymerase 1

Summary

Enhancers can regulate the promoters of their target genes over very large genomic distances. It is widely assumed that mechanisms of enhancer action involve the reorganization of three-dimensional chromatin architecture, but this is poorly understood. The predominant model involves physical enhancer-promoter interaction by looping out the intervening chromatin. However, studying the enhancer-driven activation of the Sonic hedgehog gene (Shh), we have identified a change in chromosome conformation that is incompatible with this simple looping model. Using super-resolution 3D-FISH and chromosome conformation capture, we observe a decreased spatial proximity between Shh and its enhancers during the differentiation of embryonic stem cells to neural progenitors. We show that this can be recapitulated by synthetic enhancer activation, is impeded by chromatin-bound proteins located between the enhancer and the promoter, and appears to involve the catalytic activity of poly (ADP-ribose) polymerase. Our data suggest that models of enhancer-promoter communication need to encompass chromatin conformations other than looping.

Keywords

chromatin looping
enhancer
PARP
poly(ADP-ribosyl)ation
Sonic hedgehog
TAL-effector

Cited by (0)

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Present address: Pediatric Soft Tissue Sarcoma Research Group, Hopp Children’s Cancer Center Heidelberg (KiTZ), German Cancer Research Center (DKFZ), Heidelberg, Germany

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