New Targets Identified For RNAs That Regulate Genes

[Guest guest]

New Targets Identified For RNAs That Regulate Genes

http://www.medicalnewstoday.com/articles/114264.php

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 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. 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 Schwartz; student

research assistant 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.