The genes that are involved in the development of the fetus are activated in different tissues and at different times. Their expression is carefully regulated by so-called “enhancer sequences”, which are often located far from their target genes, and requires the DNA molecule to loop around and bring them in close proximity to their target genes. Such 3D changes of the DNA are in turn controlled by other sequences called topologically associating domains (TADs). EPFL scientists have now studied the TADs involved in digit development in the fetus and have gained insights in some of the big questions surrounding them. The work is published in Genome Biology.
Now, a study by the lab of Denis Duboule at EPFL, with their colleagues at the University of Geneva, provides significant insights about TADs and how they organize DNA. “We were looking at DNA architecture and function,” says researcher Pierre Fabre, who led the project. The data indicates that these TADs can host multiple associations between Hoxd genes and up to three of their enhancers, and that disrupting the 3D structure of chromatin leads to the remodeling of TAD structure. Additionally, CTCF seems to mediate the gating of long-range DNA contacts in a boundary-selection mechanism. “The building of the recomposed TAD depends on both distinct functional and intrinsic parameters such as the genomic distance,” says Fabre.