Now, in findings that point toward an eventual gene therapy for the type of dwarfism that results when the pituitary gland is unable to manufacture the hormone, scientists at the University of Pennsylvania School of Medicine have found the mechanism that sets hGH in action. In addition, they've discerned an unusual pattern of activation in which the key mechanism operates by remote control. Their research will appear in the Friday, February 15, issue of the journal Molecular Cell. Working with transgenic mice, the Penn researchers were able to pinpoint the activation mechanism at location called hypersensitive site 1 (HS1), within the "locus control region" 15 kilobases from the hGH gene. A kilobase is a measurement representing a unit of nucleic acid. Within the microscopic realm of cells, this activation is the equivalent of unlocking the front door of a house from seven buildings away. "What we found is surprising because most genes are controlled by a promoter element adjacent to the gene, or within the gene's proximity. But in the case of this human growth hormone, the controlling mechanism is so far away there is an intervening gene between hGH and the activation site," said Stephen Liebhaber, MD, Professor of Genetics and Medicine. He is corresponding author for the study along with Nancy Cooke, MD, Professor of Medicine in the Division of Endocrinology, Diabetes and Metabolism.
The human gene cluster containing hGH includes five separate human growth genes, four of which have importance during fetal development. Only the gene hGH functions following birth, and is necessary for normal growth: Without it, humans develop a condition called pituitary dwarfism, in which their physical stature never reaches five feet.
Liebhaber, Cooke and their colleagues at Penn have been researching hGH in a series of studies and were the first to demonstrate that, unlike most hormones, hGH cannot be "turned on" merely by activating a nearby promoter element. In the present study, they've established that activating HS1 triggered a series of enzymatic changes spanning the layer of proteins and DNA (chromatin) that separate the hypersensitive activation site from the hormone promoter, eventually affecting the promoter, and ultimately opening the growth hormone itself.
"The modifications migrate through the chromatin in some way that we do not yet understand," Cooke said. Added Liebhaber, "Now we're studying the mechanism through which this signal spreads." Yugong Ho, PhD, the lead author on the paper, and Felice Elefant, PhD, both post-doctoral fellows at Penn, worked with Liebhaber and Cooke on the research.
The study was funded by the National Institutes of Health's National Institute of Child Health and Human Development.
Journal
Molecular Cell