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The selection and function of cell type-specific enhancers

Nature Reviews Molecular Cell Biology volume 16, pages 144–154 (2015)Cite this article

Subjects

Key Points

  • Enhancers are genetic elements that have major roles in determining cell type-specific gene expression patterns and responses to internal and external signals.

  • Mammalian genomes contain millions of enhancers, but only a subset of them are selected and activated in each cell type in the body.

  • Enhancer selection involves collaborative interactions between 'pioneer' or lineage-determining transcription factors. Such factors are able to prime enhancers in a cell type-specific manner by binding to closely spaced recognition motifs.

  • Signal-dependent transcription factors, such as nuclear receptors and nuclear factor-κB (NF-κB), primarily bind to regions of the genome that are primed in a cell type-specific manner by lineage-determining transcription factors. This enables such broadly expressed, signal-dependent transcription factors to regulate gene expression in a cell type-specific manner.

  • A proportion of the genome contains a very high density of marks of active enhancers. Such enhancer-rich genomic regions, which are called super-enhancers, are different in each cell type and regulate genes required for establishing cell identity and function.

  • An understanding of the mechanisms underlying the cell type-specific selection and function of enhancers will improve our understanding of the effects of natural genetic variation on complex phenotypes and diseases.

Abstract

The human body contains several hundred cell types, all of which share the same genome. In metazoans, much of the regulatory code that drives cell type-specific gene expression is located in distal elements called enhancers. Although mammalian genomes contain millions of potential enhancers, only a small subset of them is active in a given cell type. Cell type-specific enhancer selection involves the binding of lineage-determining transcription factors that prime enhancers. Signal-dependent transcription factors bind to primed enhancers, which enables these broadly expressed factors to regulate gene expression in a cell type-specific manner. The expression of genes that specify cell type identity and function is associated with densely spaced clusters of active enhancers known as super-enhancers. The functions of enhancers and super-enhancers are influenced by, and affect, higher-order genomic organization.

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Figure 1: The anatomies of poised and active enhancers.
Figure 2: Cell type-specific enhancers are marked by specific epigenomic features and chromatin accessibility.
Figure 3: Cell type-specific enhancer selection and activation.
Figure 4: Enhancer activation and function.
Figure 5: The linear and 3D organization of enhancers in the nucleus.

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Acknowledgements

The authors were primarily supported by the US National Institutes of Health (NIH) grants DK091183, CA17390 and DK063491, and the San Diego Center for Systems Biology. C.E.R. was supported by the American Heart Association (12POST11760017) and the NIH Pathway to Independence Award (1K99HL12348).

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Authors and Affiliations

  1. Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, San Diego, 92037, California, USA

    Sven Heinz & Christopher Benner

  2. Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, San Diego, 92093, California, USA

    Casey E. Romanoski & Christopher K. Glass

  3. Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, San Diego, 92093, California, USA

    Christopher K. Glass

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  1. Sven Heinz
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  2. Casey E. Romanoski
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  3. Christopher Benner
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Correspondence to Christopher K. Glass.

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PowerPoint slides

Glossary

Primed enhancers

Enhancers that have been selected by lineage-determining transcription factors and collaborating transcription factors. They are marked with characteristic histone modifications such as histone H3 lysine 4 monomethylation (H3K4me1) and H3K4me2, but do not produce enhancer RNAs.

DNase I-hypersensitive

Pertaining to genomic sites where the chromatin was made more accessible (that is, hypersensitive) to digestion by DNase I owing to the binding of regulatory proteins.

Poised enhancers

Regulatory elements that are similar to primed enhancers but that are distinguished by the presence of histone H3 lysine 27 trimethylation (H3K27me3), which must be removed to allow the transition to an active enhancer state.

Active enhancers

Enhancers that are marked with histone H3 lysine 27 acetylation (H3K27ac) marks, in addition to the marks of poised enhancers. They produce enhancer RNAs, are bound by the Mediator complex and exert regulatory functions to increase the transcription of target genes.

Latent or de novo enhancer

An inactive enhancer that requires the binding of a combination of transcription factors, including signal- dependent transcription factors, for selection.

Mediator complex

A protein complex with important roles in transcription and the 3D organization of the genome. It integrates various intracellular signals to affect the formation of the pre-initiation complex, transcription initiation and transcription elongation.

Locus control regions

Regions that confer tissue-specific expression to linked transgenes irrespective of the transgene integration site in the genome. These regions display characteristics of both enhancers and insulators.

Exosome

A protein complex involved in the quality control, maturation and degradation of various RNA transcripts, both in the nucleus and cytoplasm.

Chromosome conformation capture

(3C). A method to probe the higher-order structure of the genome by capturing and sequencing DNA sites that are spatially close to each other in the nucleus.

Topologically associated domains

(TADs). Largely self-interacting genomic domains of submegabase size that are further organized into multimegabase-sized structures called nuclear compartments. Genes within TADs are co-regulated, and their expression patterns are highly correlated.

Chromatin hubs

Nuclear domains comprised of regulatory DNA elements (locus control regions, enhancers and promoters) and genes that enable correct gene expression. The smallest unit of a hub could be a topologically associated domain, and the largest could comprise an entire nuclear compartment.

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Heinz, S., Romanoski, C., Benner, C. et al. The selection and function of cell type-specific enhancers. Nat Rev Mol Cell Biol 16, 144–154 (2015). https://doi.org/10.1038/nrm3949

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