Hepatocyte nuclear factor-1 alpha, GATA-4, and caudal related homeodomain protein Cdx2 interact functionally to modulate intestinal gene transcription. Implication for the developmental regulation of the sucrase-isomaltase gene.
Sucrase-isomaltase (SI), an intestine-specific gene, is induced in the differentiated small intestinal villous epithelium during the suckling-weaning transition in mice. We have previously identified cis-acting elements within a short evolutionarily conserved SI promoter. However, the nature and profile of expression of the interacting proteins have not been fully characterized during this developmental transition. Herein, we show that hepatocyte nuclear factor-1 alpha (HNF-1 alpha), GATA-4, and caudal related homeodomain proteins Cdx2 and Cdx1 are the primary transcription factors from the adult mouse intestinal epithelium to interact with the SIF3, GATA, and SIF1 elements of the SI promoter. We wanted to study whether HNF-1 alpha, GATA-4, and Cdx2 can cooperate in the regulation of SI gene expression. Immunolocalization experiments revealed that HNF-1 alpha is detected in rare epithelial cells of suckling mice and becomes progressively more expressed in the villous epithelial cells during the suckling-weaning transition. GATA-4 protein is expressed exclusively in villous differentiated epithelial cells of the proximal small intestine, decreases in expression in the ileum, and becomes undetectable in the colon. HNF-1 alpha, GATA-4, and Cdx2 interact in vitro and in vivo. These factors activate SI promoter activity in cotransfection experiments where GATA-4 requires the presence of both HNF-1 alpha and Cdx2. These findings imply a combinatory role of HNF-1 alpha, Cdx2, and GATA-4 for the time- and position-dependent regulation of SI transcription during development.
Boudreau
François
F
Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Rings
Edmond H H M
EH
van Wering
Herbert M
HM
Kim
Richard K
RK
Swain
Gary P
GP
Krasinski
Stephen D
SD
Moffett
Jennifer
J
Grand
Richard J
RJ
Suh
Eun Ran
ER
Traber
Peter G
PG
D000818:Animals; D001483:Base Sequence; D000071616:CDX2 Transcription Factor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050991:GATA4 Transcription Factor; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D018398:Homeodomain Proteins / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000201:enzymology* / Q000254:growth & development; D008156:Luciferases / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008871:Microvilli / Q000201:enzymology; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D013394:Sucrase-Isomaltase Complex / Q000235:genetics*; D015534:Trans-Activators; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D016335:Zinc Fingers
D000071616:CDX2 Transcription Factor; C491272:Cdx1 protein, mouse; D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; C496496:Hnf1b protein, mouse; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D008156:Luciferases; D013394:Sucrase-Isomaltase Complex