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Background  During tetrapod limb development, the HOXA13 and HOXD13 transcription factors are critical for the emergence and organization of the autopod, the most distal aspect where digits will develop. Since previous work had suggested that the  Dbx2  gene is a target of these factors, we set up to analyze in detail this potential regulatory interaction.    Results  We show that HOX13 proteins bind to mammalian‐specific sequences at the vicinity of the  Dbx2  locus that have enhancer activity in developing digits. However, the functional inactivation of the DBX2 protein did not elicit any particular phenotype related to  Hox  genes inactivation in digits, suggesting either redundant or compensatory mechanisms. We report that the neighboring  Nell2  and  Ano6  genes are also expressed in distal limb buds and are in part controlled by the same  Dbx2  enhancers despite being localized into two different topologically associating domains (TADs) flanking the  Dbx2  locus.    Conclusions  We conclude that  Hoxa13  and  Hoxd  genes cooperatively activate  Dbx2  expression in developing digits through binding to mammalian specific regulatory sequences in the  Dbx2  neighborhood. Furthermore, these enhancers can overcome TAD boundaries in either direction to co‐regulate a set of genes located in distinct chromatin domains.

Dbx2 regulation in limbs suggests inter TAD sharing of enhancers