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Insulators: exploiting transcriptional and epigenetic mechanisms

Nature Reviews Genetics volume 7, pages 703–713 (2006)Cite this article

Key Points

  • Insulators are DNA sequence elements that help to prevent inappropriate interactions between adjacent regions of the genome. There are two types of insulator — one that is involved in enhancer-blocking activity and other that provides a barrier to the spread of heterochromatin — each with distinct functions, protein components and mechanisms.

  • Enhancer-blocking insulators can prevent an enhancer from interacting with a promoter when placed between the two. This activity is position dependent; enhancer-blocking elements do not affect transcription from a flanking position.

  • Enhancer-blocking activity in Drosophila and in vertebrates correlates with the ability of the insulator involved to anchor the chromatin fibre to a fixed nuclear structure, which leads to the formation of looped domains within the nucleus. Proposed models link enhancer-blocking activity either to the topological constraints of looped chromatin domains or to some specialized property of the nucleoprotein complex at the anchoring sites.

  • Topology-based models hypothesize that some aspect of transcriptional activation is sensitive to nuclear architecture: it favours intra-loop interactions over inter-loop interactions. By placing an enhancer and promoter into separate loops, enhancer-blocking insulators reduce the chance of communication between the two.

  • Enhancer-blocking models that focus on the anchoring complex are linked to the idea that enhancers function by sending an activating signal towards the promoter that tracks along the DNA (for example, an advancing polymerase or helicase), with which the insulator structure interferes.

  • CTCF, a protein component of vertebrate enhancer-blocking insulators, has an important regulatory role at certain imprinted genes and elsewhere in the genome.

  • The phenomenon of enhancer-blocking insulation might reflect a more general role of proteins like CTCF in helping to organize large-scale chromatin interactions within the nucleus, in some cases perhaps to facilitate rather than inhibit gene expression.

  • Barrier insulators protect transgenes against chromatin-mediated silencing.

  • Barrier insulators work by altering the local balance of chromatin components in a way that favours the formation of 'active' euchromatin and/or prevents the spread of 'silenced' heterochromatic structures. Barriers achieve this by increasing the local concentration of factors that promote euchromatin formation either by direct recruitment or by tethering the insulator site to a subnuclear compartment that is rich in these factors.

  • Transition between euchromatin and heterochromatin is sharp only when a stably heterochromatic region is juxtaposed to a sequence element that can maintain itself in a euchromatic state (a barrier insulator). In all other cases the transition seems gradual at the population level as it happens at different positions in individual cells depending on the cell-specific local balance of chromatin components.

  • Barrier insulators seem to be specialized variants of other transcriptional regulatory elements such as enhancers and locus-control regions, and are based on similar principles of action and protein components.

Abstract

Insulators are DNA sequence elements that prevent inappropriate interactions between adjacent chromatin domains. One type of insulator establishes domains that separate enhancers and promoters to block their interaction, whereas a second type creates a barrier against the spread of heterochromatin. Recent studies have provided important advances in our understanding of the modes of action of both types of insulator. These new insights also suggest that the mechanisms of action of both enhancer blockers and barriers might not be unique to these types of element, but instead are adaptations of other gene-regulatory mechanisms.

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Figure 1: Testing for enhancer-blocking insulator function.
Figure 2: Insulator-body formation and enhancer blocking are closely correlated in Drosophila melanogaster.
Figure 3: The chicken β-globin locus.
Figure 4: Models for enhancer-blocking activity.
Figure 5: Problems for simple models of enhancer blocking.
Figure 6: Testing for barrier function.
Figure 7: A local balance of activities determines the extent of heterochromatin propagation.
Figure 8: Unblocked spread of heterochromatin leads to position-effect variegation.

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Acknowledgements

We thank the members of the Felsenfeld laboratory for their advice and encouragement.

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  1. National Institute of Diabetes and Digestive and Kidney Diseases, National Institues of Health, Bethesda, 20892-0540, Maryland, USA

    Miklos Gaszner & Gary Felsenfeld

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Glossary

Enhancer

A cis-acting regulatory sequence that markedly increases expression of a neighbouring gene. Enhancers are typically capable of operating over considerable distances (sometimes ∼50 kb) upstream or downstream of the gene, and in either orientation.

Silencer

A cis-acting regulatory sequence that decreases expression of a neighbouring gene.

Upstream activating sequence

A cis-acting regulatory sequence in yeast that is distinct from the promoter and increases expression of a neighbouring gene.

Enhancer-blocking insulator

A cis-acting regulatory sequence that blocks the action of an enhancer on a promoter when placed between the two, but not otherwise.

Barrier insulator

A cis-acting regulatory sequence that prevents the extension of a heterochromatic region into a euchromatic region when placed at the junction between the two.

Imprinted loci

Genes that are expressed from only one of the two parental copies, the choice being dependent on the sex of the parent from which the copy was derived.

Nucleosome

The basic structural subunit of chromatin, which consists of roughly 200 base pairs of DNA and an octamer of histone proteins.

Nuclease-hypersensitive site

Chromosomal region that is highly accessible to cleavage by deoxyribonuclease I. Such sites are associated with open chromatin conformations and transcriptional activity.

Nuclear pore complex

A large multiprotein complex that forms a channel in the nuclear envelope of eukaryotic cells. It joins the inner and outer nuclear membranes and allows transport of proteins and nucleic acids to and from the nucleus.

Locus-control region

(LCR). Originally defined as a cis-acting sequence element that confers tissue-specific, copy-number-dependent expression on a transgene. Molecular dissection of some LCRs showed them to be composite structures that are comprised of transcriptional activators and insulator elements.

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Gaszner, M., Felsenfeld, G. Insulators: exploiting transcriptional and epigenetic mechanisms. Nat Rev Genet 7, 703–713 (2006). https://doi.org/10.1038/nrg1925

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