The Conserved Sonic Hedgehog Limb Enhancer Consists of Discrete Functional Elements that Regulate Precise Spatial Expression

Publication date: 8 August 2017
Source:Cell Reports, Volume 20, Issue 6
Author(s): Laura A. Lettice, Paul Devenney, Carlo De Angelis, Robert E. Hill
Expression of sonic hedgehog (Shh) in the limb bud is regulated by an enhancer called the zone of polarizing activity regulatory sequence (ZRS), which, in evolution, belongs to an ancient group of highly conserved cis regulators found in all classes of vertebrates. Here, we examined the endogenous ZRS in mice, using genome editing to establish the relationship between enhancer composition and embryonic phenotype. We show that enhancer activity is a consolidation of distinct activity domains. Spatial restriction of Shh expression is mediated by a discrete repressor module, whereas levels of gene expression are controlled by large overlapping domains containing varying numbers of HOXD binding sites. The number of HOXD binding sites regulates expression levels incrementally. Substantial portions of conserved sequence are dispensable, indicating the presence of sequence redundancy. We propose a collective model for enhancer activity in which function is an integration of discrete expression activities and redundant components that drive robust expression.

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Teaser

Lettice et al. examine the composition of a highly conserved limb-specific enhancer, the ZRS, by dissecting the endogenous sequence using genome editing. Analysis of the resulting phenotype gives insights into the complex composition of the enhancer, which integrates discrete expression activities and redundant elements to drive accurate spatiotemporal gene expression.


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