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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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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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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DOI: https://doi.org/10.1038/82593
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