Mechanisms underlying generation of gradients in gene expression within the intestine: an analysis using transgenic mice containing fatty acid binding protein-human growth hormone fusion genes.
The intestine is lined by a continuously regenerating epithelium that maintains gradients in 'liver' fatty acid binding protein (L-FABP) gene expression along its horizontal and vertical axes, i.e., from duodenum to colon and from crypt to villus tip. To identify cis-acting DNA sequences responsible for these regional differences, we linked portions of the L-FABP gene's 5' nontranscribed region to the human growth hormone (hGH) gene and examined hGH expression in transgenic mice. Nucleotides -596 to +21 of the rat L-FABP gene correctly directed hGH expression to enterocytes and hepatocytes. However, anomalous expression was observed in small intestinal crypts, colon, and renal proximal tubular epithelial cells. Addition of nucleotides -4000 to -597 of the L-FABP gene, in either orientation, suppressed renal hGH expression and restored a nearly normal horizontal, but not a vertical, hGH gradient in the intestine. Thus, horizontal gradients of gene expression within the intestine can be maintained by orientation-independent, cis-acting suppressor elements.
Sweetser
D A
DA
Department of Biological Chemistry, Washington University School of Medicine, St. Louis, Missouri 63110.
Birkenmeier
E H
EH
Hoppe
P C
PC
McKeel
D W
DW
Gordon
J I
JI
D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D003001:Cloning, Molecular; D004848:Epithelium / Q000378:metabolism; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D013006:Growth Hormone / Q000096:biosynthesis / Q000097:blood / Q000235:genetics*; D006801:Humans; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D007413:Intestinal Mucosa / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009030:Mosaicism; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D009693:Nucleic Acid Hybridization; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D012313:RNA / Q000096:biosynthesis; D011863:Radioimmunoassay; D012045:Regulatory Sequences, Nucleic Acid; D015183:Restriction Mapping; D025521:Tumor Suppressor Proteins
D002352:Carrier Proteins; C493319:FABP1 protein, human; C107608:FABP7 protein, human; C493320:Fabp1 protein, mouse; C493321:Fabp1 protein, rat; C082667:Fabp5 protein, mouse; C086936:Fabp7 protein, mouse; C490174:Fabp7 protein, rat; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D025521:Tumor Suppressor Proteins; D012313:RNA; D013006:Growth Hormone