Hox gene clusters of jaw vertebrates display a tight genomic organization, which has no equivalent in any other bilateria genomes sequenced thus far. It was previously argued that such a topological consolidation toward a condensed, metagenic structure was due to the accumulation of long-range regulations flanking Hox loci, a phenomenon made possible by the successive genome duplications that occurred at the root of the vertebrate lineage, similar to gene neofunctionalization but applied to a coordinated multigenic system. Here, we propose that the emergence of such large vertebrate regulatory landscapes containing a range of global enhancers was greatly facilitated by the presence of topologically associating domains (TADs). These chromatin domains, mostly constitutive, may have been used as genomic niches where novel regulations could evolve due to both the preexistence of a structural backbone poised to integrate novel regulatory inputs, and a highly adaptive transcriptional readout. We propose a scenario for the coevolution of such TADs and the emergence of pleiotropy at ancestral vertebrate Hox loci.