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J. Biol. Chem., Vol. 275, Issue 34, 26637-26648, August 25, 2000

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Identification and Characterization of a 315-Base Pair Enhancer, Located More than 55 Kilobases 5' of the Apolipoprotein B Gene, That Confers Expression in the Intestine^*

Travis J. Antes^§, Sheryl A. Goodart^¶, Cathy Huynh, Meghan Sullivan, Stephen G. Young^**§§¶¶, and Beatriz Levy-Wilson^§¶¶

From the  Research Institute, Palo Alto Medical Foundation, Palo Alto, California 94301, ^§ Division of Gastroenterology, Department of Medicine, Stanford University, Stanford, California 94303, and  Gladstone Institutes for Cardiovascular Disease, ^** Cardiovascular Research Institute, and the ^§§ Department of Medicine, University of California, San Francisco, California 94141

We recently reported that an 8-kilobase (kb) region, spanning from 54 to 62 kb 5' of the human apolipoprotein B (apoB) gene, contains intestine-specific regulatory elements that control apoB expression in the intestines of transgenic mice. In this study, we further localized the apoB intestinal control region to a 3-kb segment (54 to 57 kb). DNaseI hypersensitivity studies uncovered a prominent DNaseI hypersensitivity site, located within a 315-base pair (bp) fragment at the 5'-end of the 3-kb segment, in transcriptionally active CaCo-2 cells but not in transcriptionally inactive HeLa cells. Transient transfection experiments with CaCo-2 and HepG2 cells indicated that the 315-bp fragment contained an intestine-specific enhancer, and analysis of the DNA sequence revealed putative binding sites for the tissue-specific transcription factors hepatocyte nuclear factor 3, hepatocyte nuclear factor 4, and CAAT enhancer-binding protein . Binding of these factors to the 315-bp enhancer was demonstrated in gel retardation experiments. Transfection of deletion mutants of the 315-bp enhancer revealed the relative contributions of these transcription factors in the activity of the apoB intestinal enhancer. The corresponding segment of the mouse apoB gene (located 40 to 83 kb 5' of the structural gene) exhibited a high degree of sequence conservation in the binding sites for the key transcriptional activators and also exhibited enhancer activity in transient transfection assays with CaCo-2 cells. In transgenic mouse expression studies, the 315-bp enhancer conferred intestinal expression to human apoB transgenes.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EMBL Data Bank with accession number(s) AF187727 and AF187728.

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