Penn Researchers Find Unusual Pattern to the Operation of hGH

(Philadelphia, PA) -- Scientists have long sought to determine what agent controls the production of the human growth hormone hGH, which is vital for proper physical development.

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 a 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.

 

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Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $373 million awarded in the 2015 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2015, Penn Medicine provided $253.3 million to benefit our community.

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