Chromatin changes accompany the developmental activation of insulin-like growth factor I gene transcription.
Insulin-like growth factor I (IGF-I) is a potent regulator of postnatal growth in mammals, yet little is known about the developmental control of IGF-I synthesis. We have investigated the regulation of IGF-I expression in the rat in order to gain insight into the mechanisms of growth factor induction during early postnatal life. Steady-state levels of liver IGF-I mRNA increased by more than 15-fold during the period from fetal day 18 to postnatal day 7 and reached 50% of adult values by day 14. Transcription run-on experiments using isolated hepatic nuclei and direct analysis of nuclear RNA each demonstrated a comparable rise in nascent IGF-I mRNA over the same time period. Over 90% of transcripts were directed by promoter 1, the more 5' of the two IGF-I gene promoters. By contrast IGF-II gene transcription rates and mRNA levels fell during the first 3 weeks after birth, and albumin expression rose slightly. Analysis of chromatin structure around the IGF-I gene revealed 15 DNase I-hypersensitive sites in adult rat liver in the 120 kilobases (kb) comprising the 6 exon gene and its flanking regions (8 sites within 10 kb at the 5'-end including exons 1-3, 5 sites in the 50-kb third intron, and 2 sites in the 15-kb fifth intron). During development there was a progressive appearance of DNase I-hypersensitive sites that coincided with activation of IGF-I gene expression. One site that became fully hypersensitive by postnatal day 7 was mapped by in vivo DNAse I footprinting to the proximal 200 nucleotides of promoter 1. Since serum IGF-I values rose from 10 to 120 micrograms/liter during the initial postnatal week, these results indicate that transcriptional mechanisms are principally responsible for the stimulation of IGF-I synthesis that occurs shortly after birth. Because discrete changes in chromatin organization coincided with induction of IGF-I gene transcription, it is likely that a series of developmentally modulated transcription factors are involved the activation process.
Kikuchi
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Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.
Bichell
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Rotwein
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D000818:Animals; D001483:Base Sequence; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin; D004247:DNA; D005260:Female; D005786:Gene Expression Regulation; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D008099:Liver / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic
D002843:Chromatin; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D004247:DNA