The technique, called transcriptional gene silencing (TGS), provides a new research tool to study gene function and, if continuing studies prove the concept, it could potentially become a method for therapeutic modification of the expression of disease-producing genes.
Selected for speedy publication in the August 5, 2004 edition of Science Express, the study describes, for the first time, the ability to shut down a gene literally before it is born in the nucleus of a cell. The benefit over previous gene-silencing techniques is that the nuclear version may have the potential to last considerably longer than current methods that act in the cytoplasm, the cellular area outside the nucleus.
The new technique, and older gene-silencing methods that have given rise in recent years to a multi-million dollar pharmaceutical industry, utilizes ribonucleic acid
(RNA), the cousin of DNA. Specifically, researchers use synthetic, short pieces of RNA called short interfering RNA (siRNA), to shut down genes. The synthetic versions are patterned after naturally occurring siRNA in the body that may act as a defense against gene sequences that come from viruses or other genetic parasites.
The study’s senior author, David J. Looney, M.D., associate professor of medicine at UCSD and the VA San Diego Healthcare System, said the new technique provides a new tool for research investigation aimed at elucidating the effects of different genes, and has the potential to modify gene expression in disease, such as knocking out expression of genes required for tumor growth. He cautioned, however, that further studies are needed to prove the general applicability of this concept.
An understanding of siRNA begins with a look at theway by which genes work. First, a “promoter” region within the gene must be active in order to allow the genetic information encoded in the DNA to be copied (transcribed) into a single strand of RNA called messenger RNA (mRNA). During normal transcription, the mRNA leaves the nucleus and travels to the cytoplasm of the cell, where it works with another cellular component called the ribosome to make proteins.
Technology developed about four years ago introduced synthetic siRNA into the cytoplasm of cells to silence specific genes. This technique was called post-transcriptional gene silencing (PTGS). However, PTGS is transient, with siRNA lasting only a few days in the cytoplasm. Although this is enough time for short-term research projects, the use of siRNA for therapeutic applications, such as treatment for viral infections like HIV, probably require multiple siRNA treatments or the use of a gene therapy approach.