Peering Into The Shadow World Of RNA: Crosstalk May Control The Genome

Increasingly, however, scientists are realizing that among the diverse forms of RNA, a kind of mirror molecule derived from DNA, many interact with each other and with genes directly to manage the genome from behind the scenes.

In particular, RNA produced by the vast stretches of DNA that do not code for any genes -- long considered "junk" DNA -- may in fact be serving vital duty by governing important aspects of gene expression. This type of RNA is called non-coding RNA, meaning that although it may be biologically active, it does not carry the instructions for producing any protein in the body.

The importance of better understanding these non-coding forms of RNA is underscored by the fact that they are known to play roles in such critical processes as embryonic development, cell and tissue differentiation, and cancer formation.

A review of current research in this still-developing area of biology, authored by Kazuko Nishikura, Ph.D., a professor in the Gene Expression and Regulation Program at The Wistar Institute, appears in the December issue of the journal Nature Reviews Molecular Cell Biology.

"The essence of gene regulation occurs, of course, at the level of gene transcription," Nishikura says. "Cellular machinery transcribes genetic DNA into messenger RNA from which the proteins of the body are produced. In the last several years, however, scientists investigating the biological meaning of other forms of RNA that don't code for proteins have discovered that they oversee another, more subtle level of genome control."

Nishikura's own research has for many years explored RNA editing mechanisms. In particular, she has studied an enzyme called ADAR that converts specific occurrences of a basic RNA building-block molecule called adenosine into another called inosine. In her laboratory, this simple substitution has been seen to have significant biological effects, altering the expression of certain neurotransmitter genes, for example.

Last year, this work converged with that of researchers investigating an extensive family of small molecules called microRNAs, or miRNAs, non-coding forms of RNA that appear to target and inactivate particular sets of messenger RNAs, thus preventing them from producing protein and effectively silencing the group of genes from which they were transcribed. In that study, Nishikura found that that precursor miRNAs, like messenger RNAs, are themselves subject to specific RNA editing, the result of which is to suppress -- or perhaps refocus -- miRNA expression and activity.

"MicroRNAs often target a specific set of genes," Nishikura notes. "But when editing occurs, they may target a completely different set of genes."

In recent years, Nishikura says, a growing number of scientists are discovering other links between RNA editing and the activities of different forms of non-coding RNA.

"We used to believe there were only a limited number of RNA editing sites," she says, "but now we think there may be as many as 20,000 sites involving perhaps 3,000 genes. Interestingly, most of the editing sites correlate with non-coding regions of DNA, the so-called junk DNA."

One reason for this, Nishikura and others speculate, may be that the majority of these non-coding regions are composed of repetitive sequences of DNA called transposons. The largest class of transposons, known as retrotransposons, have the remarkable ability to copy themselves into RNA, translate themselves back into DNA, and then reinsert themselves back into the DNA at the new location. If their insertion spot happens to be within the coding region for a vital gene, the result can be destruction of the gene, leading to birth defects and genetic disease.

Over evolutionary history, this ability of transposons to copy themselves to new locations has helped them to dramatically expand their representation in the mammalian genome.

"Transposons occupy as much as half of our entire genome, and they can be dangerous," Nishikura says. "As a result, mechanisms have arisen through evolution to suppress their activity. This is particularly true in the egg and sperm, where maintenance of the genome's integrity is critical."

One of these suppression mechanisms involves short interfering RNA, or siRNA, a form of non-coding RNA that specifically targets and inactivates the stretch of DNA from which it originated. In the case of transposons, this would effectively limit their ability to act, thus protecting the genome from potential disruption.

Research in the Nishikura laboratory is supported in part by grants from the National Institutes of Health, the Juvenile Diabetes Research Foundation, and the Commonwealth Universal Research Enhancement Program of the Pennsylvania Department of Health.