Polydactyly, acheiropody and long-distance regulation of the Shh gene

In this fifth lecture, the long-range regulation of the Shh gene is discussed, first by describing the work leading to the characterization of ZRS, the main sequence involved in the expression of this gene in the limbs. Next, different types of mutations affecting this ZRS sequence are described, all of which lead to a pre-axial polydactyly phenotype in which the anterior digits (the thumb) are usually duplicated or affected. The mechanism of contact between this sequence and the Shh target gene, which is located at a distance of 1 million base pairs (1Mb), is then discussed in the light of a "DNA loop extrusion" model involving the CTCF protein and the cohesin complex. In this context, the analysis of acheiropod patients (without feet or hands) is rich in readings and illustrates the existence of tethering elements whose sole function seems to be to construct chromatin architectures that will themselves promote connections between regulatory sequences and their target genes.