Penn Researchers Find Unusual Pattern to the Operation
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
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
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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