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Cell Rep. 2017 Aug 8;20(6):1396-1408. doi: 10.1016/j.celrep.2017.07.037.

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

Author information

1
MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
2
MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK. Electronic address: bob.hill@igmm.ed.ac.uk.

Abstract

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.

KEYWORDS:

HoxD genes; Shh expression; Werner mesomelic syndrome; ZRS; enhancer; genome editing; limb development; phenotype; polydactyly

PMID:
28793263
PMCID:
PMC5561167
DOI:
10.1016/j.celrep.2017.07.037
[Indexed for MEDLINE]
Free PMC Article

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