Hox genes encode transcription factors necessary for patterning the major developing anterior to posterior embryonic axis. In addition, during vertebrate evolution, various subsets of this gene family were co-opted along with the emergence of novel body structures, such as the limbs or the external genitalia. The morphogenesis of these axial structures thus relies in part upon the precisely controlled transcription of specific Hox genes, a mechanism involving multiple long-range enhancers. Recently, it was reported that such regulatory mechanisms were largely shared between different developing tissues, though with some specificities, suggesting the recruitment of ancestral regulatory modalities from one tissue to another. The analysis of chromatin architectures at HoxD and HoxA loci revealed the existence of two flanking topologically associating domains (TADs), precisely encompassing the adjacent regulatory landscapes. Here, we discuss the function of these TADs in the control of Hox gene regulation and we speculate about their capacity to serve as structural frameworks for the emergence of novel enhancers. In this view, TADs may have been used as genomic niches to evolve pleiotropic regulations found at many developmental loci.
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