Intestinal expression of the human apoA-I gene in transgenic mice is controlled by a DNA region 3' to the gene in the promoter of the adjacent convergently transcribed apoC-III gene.
The apoA-I gene in humans is principally expressed in liver and small intestine. Using transgenic mice, we previously showed that 256 bp of 5' flanking DNA was sufficient for liver expression, but as much as 5.5 kb of 5' and 4.0 kb of 3' DNA did not allow intestinal expression of the human apoA-I transgene. In the current study, a 10.5 kb DNA construction containing the apoA-I and the adjacent convergently transcribed apoC-III genes, which extends from 300 bp 5' to the apoA-I gene to 2.5 kb 5' to the apoC-III gene, produced high levels of apoA-I intestinal expression. A similar DNA construction ending 1.4 kb 5' to the apoC-III gene also allowed apoA-I intestinal expression. The DNA region from 0.2 to 1.4 kb 5' to the apoC-III gene was then cloned 1.7 kb 3' to the apoA-I gene in both orientations in the absence of apoC-III gene sequences. Intestinal apoA-I expression was also achieved with both of these constructions. In summary, these in vivo experiments suggest that the intestinal control region for the apoA-I gene is distinct from the liver control region, resides 3' to the gene in the promoter of the adjacent apoC-III gene, and has some properties of a tissue-specific enhancer.