Shadow enhancers: frequently asked questions about distributed cis-regulatory information and enhancer redundancy

Abstract

This paper, in the form of a frequently asked questions page (FAQ), addresses outstanding questions about "shadow enhancers", quasi-redundant cis-regulatory elements, and their proposed roles in transcriptional control. Questions include: What exactly are shadow enhancers? How many genes have shadow/redundant/distributed enhancers? How redundant are these elements? What is the function of distributed enhancers? How modular are enhancers? Is it useful to study a single enhancer in isolation? In addition, a revised definition of "shadow enhancers" is proposed, and possible mechanisms of shadow enhancer function and evolution are discussed.

Figure 1

Diagram of a hypothetical gene locus, illustrating how multiple distributed cis-regulatory modules can contribute to total expression of the green gene. For the purposes of this diagram, patterning is ignored, and output is considered purely quantitatively. Only regulatory elements of green are shown; although “shadow” enhancer D is nearer to the red gene, it specifically regulates green. Percentages refer to the amount of gene expression driven by each element or combination of elements, relative to the entire gene locus.

Figure 2

Possible mechanisms for the function and evolution of distributed enhancers. A: “Speed limit”: if a single module drives a sub-optimal rate of transcription, multiple modules may be required. B: “Failure rate”: if a given enhancer fails to activate transcription in a fraction of cells, a second, independently acting enhancer may significantly improve fidelity of gene expression. C: Patterning precision: two modules with overlapping patterns, but different regulatory logic, combine to produce a novel, refined gene expression pattern. D: Short-range modular interference: two enhancer modules may require a physical separation to prevent undesirable short-range positive and negative transcription factor interactions between the two modules. E: Evolvability: enhancer redundancy may create opportunities for the generation of novel patterns of gene expression. See text for a fuller discussion of these concepts.