inhibitors.
http://www.sciencedaily.com/releases/2008/07/080706194259.htm
New Targets For RNAs That Regulate Genes Identified
ScienceDaily (July 6, 2008) — Tiny strands of genetic material called
RNA -- a chemical cousin of DNA -- are emerging as major players in gene
regulation, the process inside cells that drives all biology and that
scientists seek to control in order to fight disease.
The idea that RNA (ribonucleic acid) is involved in activating and
inhibiting genes is relatively new, and it has been unclear how RNA
strands might regulate the process.
In a new study available online today and in a future issue of Nature
Structural and Molecular Biology, RNA experts at UT Southwestern Medical
Center found that, contrary to established theories, RNA can interact
with a non-gene region of DNA called a promoter region, a sequence of
DNA occurring spatially in front of an actual gene. This promoter must
be activated before a gene can be turned on.
"Our findings about the underlying mechanisms of RNA-activated gene
expression reveal a new and unexpected target for potential drug
development," said Dr. David Corey, professor of pharmacology and
biochemistry at UT Southwestern and one of the senior authors of the
study.
Genes are segments of DNA housed in the nucleus of every cell, and they
carry instructions for making proteins. Faulty or mutated genes lead to
malfunctioning, missing or overabundant proteins, and any of those
conditions can result in disease. Scientists seek to understand the
mechanisms by which genes are activated, or expressed, and turned off in
order to get a clearer picture of basic cell biology and also to develop
medical therapies that affect gene expression.
In previous studies, Dr. Corey and Dr. Bethany Janowski, assistant
professor of pharmacology at UT Southwestern and a senior author of the
current study, have shown that tiny strands of RNA can be used to
activate certain genes in cultured cancer cells. Using strands of RNA
that they manufactured in the lab, the researchers showed that the
strands regulate gene expression by somehow perturbing a delicate
mixture of proteins that surround DNA and control whether or not genes
are activated.
Until now, however, it was not clear exactly how the synthetic RNA
strands affected that mix of regulating proteins.
In the current study, also carried out in cancer cell cultures, the UT
Southwestern research team discovered an unexpected target for the
manufactured RNA. The RNA did not home in on the gene itself, but rather
on another type of RNA produced by the cell, a so-called noncoding RNA
transcript. This type of RNA is found in association with the promoter
regions that occur in front of the gene. Promoter regions, when
activated, act essentially as a "start" command for turning on genes.
The researchers found that their man-made RNA strand bound to the RNA
transcript, which then recruited certain proteins to form an RNA-protein
complex. The whole complex then bound to the promoter region, an action
that could then either activate or inhibit gene expression.
"Involvement of RNA at a gene promoter is a new concept, potentially a
big new concept," Dr. Janowski said. "Interactions at gene promoters are
critical for understanding disease, and our results bring a new
dimension to understanding how genes can be regulated."
Until recently, many scientists believed that proteins alone control
gene expression at promoters, but Drs. Corey and Janowski's results
suggest that this assumption is not necessarily true.
"By demonstrating how small RNAs can be used to recruit proteins to gene
promoters, we have provided further evidence that this phenomenon should
be in the mainstream of science," Dr. Corey said.
Although using synthetic RNA to regulate gene expression and possibly
treat disease in humans is still in the future, Dr. Corey noted that the
type of man-made RNA molecules employed by the UT Southwestern team are
already being used in human clinical trials, so progress toward the
development of gene-regulating drugs could move quickly.
Other researchers from UT Southwestern involved in the research were
lead author and student research assistant Jacob Schwartz; student
research assistant Scott Younger; and research associate Ngoc-Bich
Nguyen. Researchers from the University of Western Ontario and ISIS
Pharmaceuticals also participated.
The research was supported by the National Institutes of Health and the
Welch Foundation.
________________________________________________________________________
Adapted from materials provided by UT Southwestern Medical Center.
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