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Targeted inversion of a polar silencer within the HoxD complex re-allocates domains of enhancer sharing

Nature Genetics volume 26, pages 451–454 (2000)Cite this article

Abstract

Mammalian Hox genes are clustered at four genomic loci. During development, neighbouring genes are coordinately regulated by global enhancer sequences, which control multiple genes at once, as exemplified by the expression of series of contiguous Hoxd genes in either limbs or gut. The link between vertebrate Hox gene transcription and their clustered distribution is poorly understood. Experimental and comparative approaches have revealed that various mechanisms, such as gene clustering or global enhancer sequences, might have constrained this genomic organization and stabilized it throughout evolution1,2,3. To understand what restricts the effect of a particular enhancer to a precise set of genes, we generated a loxP/Cre-mediated targeted inversion within the HoxD cluster. Mice carrying the inversion showed a reciprocal re-assignment of the limb versus gut regulatory specificities, suggesting the presence of a silencer element with a unidirectional property. This polar silencer appears to limit the number of genes that respond to one type of regulation and thus indicates how separate regulatory domains may be implemented within intricate gene clusters.

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Figure 1: Targeted inversion in the HoxD complex.
Figure 2: Limb alterations in animals with either the inverted or the non-inverted allele.
Figure 3: Expression of Hoxd genes in developing limbs, from the inverted and non-inverted alleles.
Figure 4: Expression of Hoxd genes in developing intestinal hernia, in either the inverted or non-inverted alleles.
Figure 5: Scheme of global gene regulation in posterior HoxD complex.
Figure 6: Expression of either Hoxd genes or targeted transgenes in distal limbs and hernial gut, after rearrangements of the Hoxd complex.

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Acknowledgements

We thank M. Friedli for technical assistance; members of the laboratory for comments and reagents; and M. Levine for comments. This work was supported by funds from the Canton de Genève, the Swiss National Research Fund, the Claraz, Latsis, Cloetta and Louis-Jeantet foundations.

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  1. Department of Zoology and Animal Biology, University of Geneva, Sciences III, Geneva, Switzerland

    Marie Kmita, Takashi Kondo & Denis Duboule

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  1. Marie Kmita
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Correspondence to Denis Duboule.

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Kmita, M., Kondo, T. & Duboule, D. Targeted inversion of a polar silencer within the HoxD complex re-allocates domains of enhancer sharing. Nat Genet 26, 451–454 (2000). https://doi.org/10.1038/82593

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