Enhancer redundancy in development and disease

Abstract

Shadow enhancers are seemingly redundant transcriptional cis-regulatory elements that regulate the same gene and drive overlapping expression patterns. Recent studies have shown that shadow enhancers are remarkably abundant and control most developmental gene expression in both invertebrates and vertebrates, including mammals. Shadow enhancers might provide an important mechanism for buffering gene expression against mutations in non-coding regulatory regions of genes implicated in human disease. Technological advances in genome editing and live imaging have shed light on how shadow enhancers establish precise gene expression patterns and confer phenotypic robustness. Shadow enhancers can interact in complex ways and may also help to drive the formation of transcriptional hubs within the nucleus. Despite their apparent redundancy, the prevalence and evolutionary conservation of shadow enhancers underscore their key role in emerging metazoan gene regulatory networks.

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Fig. 1: Shadow enhancers confer phenotypic robustness in mammals.
Fig. 2: Independent TF inputs to shadow enhancers lead to more robust transcriptional output.
Fig. 3: Shadow enhancers can combine in complex and varied ways.
Fig. 4: Interactions of shadow enhancers with target promoters.
Fig. 5: Shadow enhancers buffer gene expression against non-coding mutations in disease-causing genes.
Fig. 6: Many evolutionary routes potentially lead to shadow enhancer birth.

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Acknowledgements

This work was supported by US National Institutes of Health grants R01HD095246 (to Z.W.) and R00HG009682 (to E.Z.K). R.W. was supported by an ARCS Foundation award. The authors thank A. Visel, D. Dickel, A. Stark, D. Shlyueva and the reviewers for helpful comments on the manuscript.

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All authors researched the literature and wrote the article. E.Z.K., R.W. and Z.W. substantially contributed to discussions of the content, and reviewed and/or edited the manuscript before submission.

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Correspondence to Evgeny Z. Kvon or Zeba Wunderlich.

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Glossary

Expression domains

The specific tissues or cell types where an enhancer drives expression of its target gene.

Phenotypic robustness

The ability of a system to reliably produce a wild-type phenotype in the presence of environmental (for example, temperature) or genetic (for example, decreased expression levels of an upstream transcription factor) stress.

Evolutionary constraint

Factors that serve to limit the divergence of a particular phenotype; conserved DNA sequences are interpreted as evidence of evolutionary constraint.

Super-enhancers or stretch enhancers

Clusters of enhancers that are strongly occupied by transcription factors, co-activators or modified histones (as measured by chromatin immunoprecipitation followed by sequencing) and that control key cell identity genes.

Enhancer-derived RNAs

(eRNAs). Short, non-coding RNAs that are transcribed from the DNA of enhancer sequences and whose transcription correlates with enhancer activity.

Haplosufficiency

A property of an allele whereby a single copy of that allele in a diploid organism is sufficient to drive a wild-type phenotype.

Expression noise

Variability in gene expression across either time or space, owing to the stochastic nature of the molecular interactions underlying gene expression.

Quenching

A form of repression whereby the binding of repressive transcription factors within an enhancer sequence blocks the binding of activating transcription factors.

Transcription bursts

Periods of rapid transcription interspersed with periods of transcriptional silence.

Transcriptional hubs

Three-dimensional nuclear compartments (more than 300 nm) formed around actively transcribed genes with a high local concentration of transcription factors, co-activators, RNA polymerase II and other components of the core transcriptional machinery.

Ultraconserved enhancers

Enhancers overlapping ‘ultraconserved’ sequences, which are stretches of DNA that share perfect sequence conservation between mouse, rat and human.

Transposon co-option

The process by which a transposon changes its function (for example, becomes a new gene or enhancer) through the introduction of sequence mutations.

Topologically associating domain

Large genomic domains (~1 Mb) that display more frequent physical contacts between sequences within the same domain than between sequences from different domains.

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Kvon, E.Z., Waymack, R., Elabd, M.G. et al. Enhancer redundancy in development and disease. Nat Rev Genet (2021). https://doi.org/10.1038/s41576-020-00311-x

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