Defining Human Insulin-like Growth Factor 1 Gene Regulation
AJP Endocrinology and Metabolism
Published online on July 12, 2016
Abstract
Growth hormone (GH) plays an essential role in controlling somatic growth and in regulating multiple physiological processes in humans and other species. Insulin-like growth factor 1 (IGF1), a conserved secreted 70-amino acid peptide, is a critical mediator of many of the biological effects of GH. Previous studies have demonstrated that GH rapidly and potently promotes IGF1 gene expression in rodents and in some other mammals through the transcription factor Stat5b, leading to accumulation of IGF1 mRNAs and production of IGF1. Despite this progress, very little is known about how GH or other trophic factors control human IGF1 gene expression, in large part because of the absence of any cellular model systems that robustly express IGF1. Here we have addressed mechanisms of regulation of human IGF1 by GH after generating cell lines in which the IGF1 chromosomal locus has been incorporated into a mouse cell line. Using these cells we find that physiological levels of GH rapidly stimulate human IGF1 gene transcription, and identify several potential transcriptional enhancers in chromatin that bind Stat5b in a GH-regulated way. Each of the putative enhancers also activates a human IGF1 gene promoter in reconstitution experiments in the presence of the GH receptor, Stat5b, and GH. We thus have developed a novel experimental platform that now may be used to determine how human IGF1 gene expression is controlled under different physiological and pathological conditions.