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Inversion-induced disruption of the Hoxd cluster leads to the partition of regulatory landscapes

Nature Genetics volume 37, pages 889–893 (2005)Cite this article

Abstract

The developmental regulation of vertebrate Hox gene transcription relies on the interplay between local and long-range controls. To study this complex genomic organization, we designed a strategy combining meiotic and targeted recombinations to induce large chromosomal rearrangements in vivo without manipulating embryonic stem cells. With this simple approach (called STRING), we engineered a large 7-cM inversion, which split the Hoxd cluster into two independent pieces. Expression analyses showed a partition of global enhancers, allowing for their precise topographic allocation on either side of the cluster. Such a functional organization probably contributed to keeping these genes clustered in the course of vertebrate evolution. This approach can be used to study the relationship between genome architecture and gene expression, such as the effects of genome rearrangements in human diseases or during evolution.

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Figure 1: The STRING approach.
Figure 2: Efficiency of targeted inversion around the Hoxd locus.
Figure 3: A 7-cM large inversion between Itga6 and Hoxd.
Figure 4: Targeted split of the Hoxd gene cluster.
Figure 5: Remote large-scale enhancers flanking the Hoxd cluster define overlapping regulatory landscapes.

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Acknowledgements

We thank A. Sonnenberg, U. Gunthert, J. Zakany and J. Cobb for gifts of mice and advice for genotyping; G. Zacchetti for in situ probes; F. Chabaud for help with mouse fibroblasts; C. Hinard for the chromosome FISH analysis; and J. Zakany for comments on this manuscript. This work was supported by funds from the canton de Genève, the Claraz and Louis-Jeantet foundations, the Swiss National Research Fund, the National Center for Competence in Research 'Frontiers in Genetics' and the European Union programmes 'Eumorphia' and 'Cells to Organs'.

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Authors and Affiliations

  1. Department of Zoology and Animal Biology University of Geneva, National Research Centre 'Frontiers in Genetics', Sciences III, Quai Ernest Ansermet 30, Geneva, 4, 1211, Switzerland

    François Spitz, Carole Herkenne & Denis Duboule

  2. Department of Medical Genetics and Development, Medical School, University of Geneva and Service of Medical Genetics, Geneva University Hospitals, Rue Michel Servet 1, Geneva, 1211, Switzerland

    Michael A Morris

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  1. François Spitz
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Correspondence to Denis Duboule.

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Supplementary information

Supplementary Table 1

Sequences of primers used to genotype the different alleles. (PDF 53 kb)

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Spitz, F., Herkenne, C., Morris, M. et al. Inversion-induced disruption of the Hoxd cluster leads to the partition of regulatory landscapes. Nat Genet 37, 889–893 (2005). https://doi.org/10.1038/ng1597

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