title: A duodenum-specific enhancer regulates expression along three axes in the small intestine.
abstract: Adenosine deaminase (ADA) is expressed at high levels in the epithelium of proximal small intestine. Transgenic mice were used to characterize the regulatory region governing this activation. A duodenum-specific enhancer is located in intron 2 of the human ADA gene at the central site among a cluster of seven DNase I-hypersensitive sites present in duodenal DNA. Flanking DNA, including the remaining hypersensitive sites, is required for consistent high-level enhancer function. The enhancer activates expression in a pattern identical to endogenous ADA along both the anterior-posterior axis of the small intestine and the crypt-villus differentiation axis of the intestinal epithelium. Timing of activation by the central enhancer mimics endogenous mouse ADA activation, occurring at 2-3 wk of age. However, two upstream DNA segments, one proximal and one distal, collaborate to change enhancer activation to a perinatal time point. Studies with duodenal nuclear extracts identified five distinct DNase I footprints within the enhancer. Protected regions encompass six putative binding sites for the transcription factor PDX-1, as well as proposed CDX, hepatocyte nuclear factor-4, and GATA-type sites.
authors.affiliation: Division of Developmental Biology, Department of Pediatrics, University of Cincinnati College of Medicine and Children's Hospital Research Foundation, Cincinnati, Ohio 45229, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Dusing
authors.forename: A G
authors.initials: AG
authors.lastname: Brickner
authors.forename: S Y
authors.initials: SY
authors.lastname: Lowe
authors.forename: M B
authors.initials: MB
authors.lastname: Cohen
authors.forename: D A
authors.initials: DA
authors.lastname: Wiginton
mesh_terms: D000243:Adenosine Deaminase / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001665:Binding Sites / Q000235:genetics; D002795:Choline O-Acetyltransferase / Q000235:genetics; D002874:Chromosome Mapping; D018983:DNA Footprinting; D004268:DNA-Binding Proteins; D003850:Deoxyribonuclease I; D004386:Duodenum / Q000502:physiology*; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D051557:Hepatocyte Nuclear Factor 4; D018398:Homeodomain Proteins; D017403:In Situ Hybridization; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics; D019076:Transgenes
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D051557:Hepatocyte Nuclear Factor 4; D018398:Homeodomain Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; C501970:Tcfl4 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C084010:pancreatic and duodenal homeobox 1 protein; D002795:Choline O-Acetyltransferase; D003850:Deoxyribonuclease I; D000243:Adenosine Deaminase