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Enhancer function: new insights into the regulation of tissue-specific gene expression

Key Points

  • Enhancers are specified by distinct chromatin features that may contribute to the repertoire of epigenetic mechanisms responsible for cellular memory and cell type-specific gene expression.

  • The presence of H3.3/H2A.Z histone variants contributes to nucleosome plasticity at enhancers and facilitates transcription factor binding.

  • H3K4me1 (histone 3 monomethylated at lysine 4) appears to be a key chromatin modification at many enhancers. These enhancer sequences are further marked by combinatorial patterns of histone modification or occupancy by CBP or p300, indicative of their context-dependent function.

  • The presence of H3K27ac (histone 3 acetylated at lysine 27) or H3K27me3 (histone 3 trimethylated at lysine 27) specifies whether an enhancer is active or poised for activation, respectively.

  • Extensive intra- and interchromosomal interactions between enhancers and promoters are detected at many co-regulated genes during development.

  • Chromatin looping between enhancer and promoter are in part mediated by the interaction between specific transcription factors, CCCTC-binding factor, mediator and/or the cohesin complex.

  • Transcription of long intergenic ncRNAs from some enhancers can regulate expression of their neighbouring genes by targeting specific chromatin modifying factors to their promoter regions.

  • The FOS-like antigen 1 (FOSL1) enhancer appears to facilitate the recruitment of histone-modifying complexes that trigger RNA polymerase II release from promoter-proximal pausing, rather than initiation, and productive transcription from its cognate promoter.

Abstract

Enhancer function underlies regulatory processes by which cells establish patterns of gene expression. Recent results suggest that many enhancers are specified by particular chromatin marks in pluripotent cells, which may be modified later in development to alter patterns of gene expression and cell differentiation choices. These marks may contribute to the repertoire of epigenetic mechanisms responsible for cellular memory and determine the timing of transcription factor accessibility to the enhancer. Mechanistically, cohesin and non-coding RNAs are emerging as crucial players responsible for facilitating enhancer–promoter interactions at some genes. Surprisingly, these interactions may be required not only to facilitate initiation of transcription but also to activate the release of RNA polymerase II (RNAPII) from promoter-proximal pausing.

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Figure 1: Transcriptional regulatory elements in metazoans.
Figure 2: Many functional enhancers contain dynamic nucleosomes.
Figure 3: Chromatin signatures at enhancers act as epigenetic signals for gene induction.
Figure 4: Cohesins stabilize enhancer–promoter interactions by different strategies.
Figure 5: Non-coding RNAs mediate enhancer function.
Figure 6: Crosstalk between histones at enhancers and promoters regulates RNAPII elongation.

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Acknowledgements

We would like to thank A. Wood and C. Hou for suggestions on the manuscript. Work in the authors' laboratory is supported by the Public Health Service Award GM35463 from the US National Institutes of Health and by the National Science Foundation Award MCB-0618972.

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Glossary

Mediator

The ~30-subunit co-activator complex that is necessary for successful transcription at class II promoters of metazoans genes. Mediator coordinates the signals between enhancers and the general transcription machinery through its interaction with RNA polymerase II and site-specific factors.

Basal transcription

Low levels of transcription that can occur in the absence of an activator.

Pioneer transcription factor

The first transcription factor to access a regulatory region of tissue-specific genes. Its association with chromatin initiates decompaction of nucleosomes and the cascade of events that culminates in transcriptional activation.

Chromosome conformation capture

(3C). A technique used to study long-distance interactions between genomic regions, which in turn can be used to study the three-dimensional architecture of chromosomes within a cell nucleus.

Locus control region

(LCR). Cis-acting element that organizes a gene cluster into an active chromatin domain and enhances transcription in a tissue-specific manner.

Transcription factory

A nuclear subcompartment that is rich in RNA polymerases and transcription factors where dispersed genes gather to become active.

GENCODE

The GENCODE annotation aims to identify and map all gene features within the ENCODE (Encyclopedia of DNA Elements) regions by experimental validation. The results will include protein-coding genes with alternatively transcribed variants, non-coding RNAs and pseudogenes.

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Ong, CT., Corces, V. Enhancer function: new insights into the regulation of tissue-specific gene expression. Nat Rev Genet 12, 283–293 (2011). https://doi.org/10.1038/nrg2957

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