The constrained architecture of mammalian Hox gene clusters

Darbellay, Fabrice; Bochaton, Célia; Lopez-Delisle, Lucille; Mascrez, Bénédicte; Tschopp, Patrick; Delpretti, Saskia; Zakany, Jozsef; Duboule, Denis

doi:10.1073/pnas.1904602116

Title: The constrained architecture of mammalian Hox gene clusters

Journal Article · 17 June 2019 · Proceedings of the National Academy of Sciences of the United States of America

DOI: https://doi.org/10.1073/pnas.1904602116 · OSTI ID:1560602

^[1]; Bochaton, Célia ^[1];

^[1]; Mascrez, Bénédicte ^[2]; Tschopp, Patrick ^[2]; Delpretti, Saskia ^[1]; Zakany, Jozsef ^[2]; Duboule, Denis ^[3]

Federal Inst. of Technology, Lausanne (Switzerland)
Univ. of Geneva (Switzerland)
Federal Inst. of Technology, Lausanne (Switzerland); Univ. of Geneva (Switzerland); Collège de France, Paris (France)

In many animal species with a bilateral symmetry, Hox genes are clustered either at one or at several genomic loci. This organization has a functional relevance, as the transcriptional control applied to each gene depends upon its relative position within the gene cluster. It was previously noted that vertebrate Hox clusters display a much higher level of genomic organization than their invertebrate counterparts. The former are always more compact than the latter, they are generally devoid of repeats and of interspersed genes, and all genes are transcribed by the same DNA strand, suggesting that particular factors constrained these clusters toward a tighter structure during the evolution of the vertebrate lineage. Here, we investigate the importance of uniform transcriptional orientation by engineering several alleles within the HoxD cluster, such as to invert one or several transcription units, with or without a neighboring CTCF site. We observe that the association between the tight structure of mammalian Hoxclusters and their regulation makes inversions likely detrimental to the proper implementation of this complex genetic system. We propose that the consolidation of Hox clusters in vertebrates, including transcriptional polarity, evolved in conjunction with the emergence of global gene regulation via the flanking regulatory landscapes, to optimize a coordinated response of selected subsets of target genes in cis.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC); European Research Council (ERC)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1560602

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, Issue 27; ISSN 0027-8424

Publisher:: National Academy of Sciences, Washington, DC (United States)Copyright Statement

Country of Publication:: United States

Language:: English

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CYTOGENETIC ANALYSIS OF CHROMOSOME 3 IN DROSOPHILA MELANOGASTER : THE HOMOEOTIC GENE COMPLEX IN POLYTENE CHROMOSOME INTERVAL 84A-B Kaufman, Thomas C.; Lewis, Ricki; Wakimoto, Barbara Genetics, Vol. 94, Issue 1 https://doi.org/10.1093/genetics/94.1.115	journal	January 1980
Corrigendum: CTCF-mediated topological boundaries during development foster appropriate gene regulation Narendra, Varun; Bulajić, Milia; Dekker, Job Genes & Development, Vol. 31, Issue 16 https://doi.org/10.1101/gad.306829.117	journal	August 2017
Hox11 paralogous genes are essential for metanephric kidney induction Wellik, D. M. Genes & Development, Vol. 16, Issue 11 https://doi.org/10.1101/gad.993302	journal	June 2002
A Switch Between Topological Domains Underlies HoxD Genes Collinearity in Mouse Limbs Andrey, G.; Montavon, T.; Mascrez, B. Science, Vol. 340, Issue 6137 https://doi.org/10.1126/science.1234167	journal	June 2013
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The rise and fall of Hox gene clusters Duboule, D. Development, Vol. 134, Issue 14 https://doi.org/10.1242/dev.001065	journal	June 2007
A mutational analysis of the 5′ HoxD genes: dissection of genetic interactions during limb development in the mouse Davis, A. P.; Capecchi, M. R. Development, Vol. 122, Issue 4 https://doi.org/10.1242/dev.122.4.1175	journal	April 1996
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Distinct Roles and Regulations for Hoxd Genes in Metanephric Kidney Development Di-Poï, Nicolas; Zákány, József; Duboule, Denis PLoS Genetics, Vol. preprint, Issue 2007 https://doi.org/10.1371/journal.pgen.0030232.eor	journal	January 2005
Transcriptional interference networks coordinate the expression of functionally related genes clustered in the same genomic loci Boldogköi, Zsolt Frontiers in Genetics, Vol. 3 https://doi.org/10.3389/fgene.2012.00122	journal	January 2012
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