By Avigayil Kadesh
A unique discovery about the mechanics of one of life’s most basic processes – transcription of the genetic code – has put Israeli researchers in the spotlight.
In Prof. Rivka Dikstein’s biochemistry lab at the
Weizmann Institute of Science in Rehovot, postdoctoral fellow Nadav Marbach-Bar carried out a study that revealed that genetic transcription resembles road traffic, including traffic jams, accidents and a police force that controls the flow of vehicles.
This surprising finding, reported recently in
Nature Communications, could one day lead to the development of a new generation of drugs for a variety of disorders.
All the cells of the body are constantly replicating themselves according to a genetic code stored in DNA strands. The coded instructions are first transcribed, via enzymes, into a single-stranded RNA molecule. Marbach-Bar specifically tracked the transcription of genes coding for tiny regulatory molecules called microRNAs, which were discovered only in the 1990s.
The process was found to be similar to the flow of vehicular traffic: Transcribing enzymes are like cars driving along a road of genes, creating molecules that will later be translated into the proteins critical to cell life.
Just as on a real road, the surest way for the enzymes to reach their destination – making microRNA -- is to have a “cop” maintaining reasonable distances between “vehicles.”
When the experimenters launched enzymes in bursts, they observed that fewer microRNA were created. When they launched enzymes at greater intervals, the production of microRNA was more efficient.
This is because when the enzymes were launched in rapid succession, they ended up in a traffic jam of sorts. The first enzyme paused at a “road bump” – a molecular signal that creates a pause in transcription – and the enzymes that followed too closely behind crashed into it, falling off the gene road entirely.
In contrast, when the enzymes were launched one by one, each had sufficient time to pause at the “bump” and to succeed at creating a microRNA molecule.
Clues to cancer and inflammation
Dikstein says the findings are unique and will likely have many potential applications, though the study did not address these directly.
“Companies or laboratories interested in designing small RNA molecules for treatment are likely to take these findings into consideration,” says Dikstein, who occupies the Ruth and Leonard Simon Professorial Chair of Cancer Research and studies the regulation of gene expression at various levels.
After she presented the microRNA study at an international conference in Utah in October 2012, people from universities and institutes from all over the world requested copies of the paper. She also presented it at a conference at Cold Spring Laboratory in New York in August 2013.
The novelty of their discovery is that what happens at the beginning of the gene transcription process affects results at the end of the process.
Now that the Weizmann scientists have explained how this works in microRNA, they are attempting to see if the same “traffic pattern” exists in the transcription of other genes as well.
“We believe this is a general phenomenon,” says Dikstein. “This idea was already suggested and has been shown in a few examples in bacteria, but this is the first time such a mechanism has been shown for genes in higher organisms such as humans.”
Because they can help control gene expression, microRNAs hold promise for serving as future therapeutics – for example, blocking the activity of cancer-causing genes.
“Traffic jams” in gene transcription also could help explain how the inflammatory process regulates itself.
When the body is invaded by a virus or bacterium, the release of anti-inflammatory microRNAs is temporarily suspended. The researchers believe this is because inflammation increases the launch rate of transcription enzymes, creating traffic jams that reduce microRNA production. This reduction gives the inflammation a chance to perform its healing function before it is terminated by the microRNA.
In addition to Dikstein and Marbach-Bar, the research team included Amitai Ben-Noon, Shaked Ashkenazi, Ana Tamarkin-Ben Harush, Dr. Tali Avnit-Sagi and Prof. Michael Walker.