Temporal regulation of adenosine deaminase (ADA) enhancer function in intestinal epithelium

The adenosine deaminase (ADA) gene is expressed in a defined spatiotemporal pattern in the intestine where high‐level expression is limited to the villous epithelium of the duodenum. In mice, activation of ADA intestinal expression coincides with the final maturation of the intestine's crypt‐villus structures at 2–3 weeks post‐partum. A regulatory module that controls ADA intestinal expression exists in the second intron of the human ADA gene where it is associated with a series of duodenal‐specific hypersensitive sites (HSs). A potent duodenum‐specific enhancer is associated with HS‐D. In the adjacent HS‐C, a temporal regulatory element has been identified that has no inherent enhancer activity of its own, but controls the timing of enhancer activation. This temporal element has been DNaseI footprinted and binding sites for several factors, including YY1, NFI and the Onecut (OC) family, have been identified. The functional role of these factors in temporal regulation of intestinal ADA expression is being investigated by mutational studies in transgenic mice. Molecular studies are also under way to examine protein‐protein interactions in the regulatory module. (Supported by NIH/NIDDK grant #DK‐52343)