The regulatory landscape of the Dlx gene system in branchial arches: Shared characteristics among Dlx bigene clusters and evolution.

The mammalian Dlx genes encode homeobox-type transcription factors and are physically organized as convergent bigene clusters. The paired Dlx genes share tissue specificity in the expression profile. Genetic regulatory mechanisms, such as intergenic enhancer sharing between paired Dlx genes, have been proposed to explain this conservation of bigene structure. All mammalian Dlx genes have expression and function in developing craniofacial structures, especially in the first and second pharyngeal arches (branchial arches). Each Dlx cluster (Dlx1/2, Dlx3/4, and Dlx5/6) has overlapping, nested expression in the branchial arches which is called the "Dlx code" and plays a key role in organizing craniofacial structure and evolution. Here we summarize cis-regulatory studies on branchial arch expression of the three Dlx bigene clusters and show some shared characteristics among the clusters, including cis-regulatory motifs, TAD (Topologically Associating Domain) boundaries, CTCF loops, and distal enhancer landscapes, together with a molecular condensate model for activation of the Dlx bigene cluster.