Liver-specific and proliferation-induced deoxyribonuclease I hypersensitive sites in the mouse insulin-like growth factor binding protein-1 gene.
The insulin-like growth factor binding protein-1 (IGFBP-1) gene is highly expressed in fetal, perinatal, and regenerating liver. Up-regulation is transcriptionally mediated in regenerating liver and occurs in the first few minutes to hours after partial hepatectomy. In transgenic mice a 970-bp region from -776 to +151 of the IGFBP-1 promoter was sufficient for tissue-specific and induced expression of the gene in fetal and hepatectomized livers. However weak and/or poorly regulated expression in some transgenic lines suggested the existence of other regulatory regions. Here, genomic clones containing large regions 5' of the mouse IGFBP-1 gene sequence were isolated, subcloned, and sequenced. Deoxyribonuclease I (DNaseI) hypersensitivity analyses identified clusters of tissue-specific nuclease-sensitive sites in the promoter region, -100 to -300, -2,300, -3,100, and -5,000 along with other weak sites. After partial hepatectomy, enhanced sensitivity and/or novel sites were detected in the -100/-300, -5,000, and -3,100 regions, the promoter region remaining the most hypersensitive. A subset of these sites was present in fetal and perinatal livers. Novel tissue-specific sites that interacted with C/EBP and hepatic nuclear factor 3 (HNF3) transcription factors were identified in the -3,100 region. A hepatectomy-induced DNA binding complex containing the transcription factor USF1 was identified within the -100 to -300 region of the promoter. These results suggested that a complex array of tissue-specific and hepatic proliferation-induced transcription factors combine to regulate both the proximal promoter and more distal regulatory elements of the IGFBP-1 gene.
Crissey
M A
MA
Department of Genetics, Division of Gastroenterology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Leu
J I
JI
DeAngelis
R A
RA
Greenbaum
L E
LE
Scearce
L M
LM
Kovalovich
K
K
Taub
R
R
D000818:Animals; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular; D003001:Cloning, Molecular; D003850:Deoxyribonuclease I; D005333:Fetus; D018507:Gene Expression Regulation, Developmental; D006498:Hepatectomy; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics*; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000166:cytology* / Q000378:metabolism*; D008113:Liver Neoplasms; D008115:Liver Regeneration; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000096:biosynthesis; D012045:Regulatory Sequences, Nucleic Acid; D015183:Restriction Mapping; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D013154:Spleen / Q000378:metabolism; D013379:Substrate Specificity; D014162:Transfection; D014407:Tumor Cells, Cultured
D018970:Insulin-Like Growth Factor Binding Protein 1; D011994:Recombinant Proteins; D003850:Deoxyribonuclease I