Our current work in the Duboule Lab is focused on two projects.
The first is analysis of Hox gene function during the formation of the urogenital system. The formation of these tissues begins around embryonic day E10.5, which is concurrent with the establishment of Hox gene expression domains along the mesoderm, from which these organs arise. Interestingly, the anterior boundaries of HoxD and HoxA genes delineate the boundaries of nearly every portion of the urinary system and male and female reproductive systems. Loss-of-Function mutations in the HoxA or HoxD clusters cause homeotic transformations in these tissues, several of which are very similar or the same as human congenital malformations. I am working to understand how the HoxD genes are regulated during the formation and maintenance of these structures.
The second project is focused on the gene Hoxd13 during formation of the handplate (autopod). The expression of this gene is very tightly controlled during limb formation because premature activation of Hoxd13 abruptly terminates the collinearity program resulting in abbreviated arms and legs. Our previous work has shown that a chromatin structure sequesters Hoxd13 from the activating mechanism that works on the adjacent genes in the cluster. The same work has shown that Hoxd13 is in constitutive contact with many positions in the adjacent gene desert but when the gene is activated, a few additional elements gain chromatin contact with Hoxd13. This system represents an excellent model for how enhancers act on specific genes and how enhancer elements control the properties of the adjacent chromatin.