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 e xpressed in fetal, perinatal, and regenerating liver, Up-regulation is tran scriptionally mediated in regenerating liver and occurs in the first few mi nutes 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-specif ic and induced expression of the gene in fetal and hepatectomized livers. H owever weak and/or poorly regulated expression in some transgenic lines sug gested the existence of other regulatory regions. Here, genomic clones cont aining large regions 5' of the mouse IGFBP-1 gene sequence were isolated, s ubcloned, and sequenced. Deoxyribonuclease I (DNaseI) hypersensitivity anal yses 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 s ites were detected in the -100/-300, -5,000, and -3,100 regions, the promot er region remaining the most hypersensitive. A subset of these sites was pr esent in fetal and perinatal livers. Novel tissue-specific sites that inter acted with C/EBP and hepatic nuclear factor 3 (HNF3) transcription factors were identified in the -3,100 region. A hepatectomy-induced DNA binding com plex containing the transcription factor USF1 was identified within the -10 0 to -300 region of the promoter. These results suggested that a complex ar ray of tissue-specific and hepatic proliferation-induced transcription fact ors combine to regulate both the proximal promoter and more distal regulato ry elements of the IGFBP-1 gene.