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Proc Natl Acad Sci U S A. 2019 Jul 2;116(27):13424-13433. doi: 10.1073/pnas.1904602116. Epub 2019 Jun 17.

The constrained architecture of mammalian Hox gene clusters.

Author information

School of Life Sciences, Federal Institute of Technology, Lausanne, 1015 Lausanne, Switzerland.
Department of Genetics and Evolution, University of Geneva, 1211 Geneva 4, Switzerland.
School of Life Sciences, Federal Institute of Technology, Lausanne, 1015 Lausanne, Switzerland;
Collège de France, 75005, 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 Hox clusters 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.


CRISPR-Cas9; CTCF; Hox; Polycomb; transcription

Conflict of interest statement

The authors declare no conflict of interest.

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