Gene regulation via dynamic change of chromosomal conformation of remote enhancers

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Sonic hedgehog(Shh) encodes a signaling protein that plays pivotal roles in vertebrate development. Comparison of genomic sequences across mammalian species and teleost fishes revealed four conserved non-coding sequences(CNCSs) that cluster in a region 600 to 900 kb upstream of the Shh promoter. These CNCSs drive regional transgenic lacZ reporter expression in the limb bud and the epithelial lining of the oral cavity, pharynx and larynx(lung/gut), recapitulating the endogenous Shh expression. Targeted elimination of each of the four CNCSs from the mouse genome results in loss of endogenous Shh expression in specific regions, corresponding to the expression pattern of the transgenic LacZ reporter, and leads to regional-specific defect. The results indicate that these CNCSs are tissue-specific long-range Shh enhancers. The 3D-FISH and 3C analyses showed that the Shh promoter-enhancer occurs in a tissue specific manner. Thus, chromosome dynamics is a common mechanism to regulate the tissue-specific Shh expression by the long-range enhancers.