MicroRNAs are the newest kid on the genetic block. By regulating the unzipping of genetic information, these tiny molecules have set the scientific world alight with such wide-ranging applications as onions that can’t make you cry and potential new therapeutic treatments for viral infections, cancer and degenerative diseases. But the question remains: How do they work?
In research to appear in the June 17 advance online issue of Nature, Robert B. Darnell, head of the Laboratory of Molecular Neuro-oncology, and his team at Rockefeller University provide a long-awaited key clue to answering that question. By using a technique that molecularly cements proteins to RNAs, the team has decoded a map of microRNA-messenger RNA interactions in the brain, an advance that holds promise for biology and human disease, for example by silencing trouble-making genes linked to disease.
MicroRNAs rewrote the rules of gene expression in 2001 when they were found to bind to messenger RNA and shut down protein production, called RNA interference. By 2006, when the Nobel Prize in medicine was given for the discovery of RNA interference, scientists around the globe had even narrowed down microRNAs’ primary site of action to somewhere around the end of the RNA transcript. What scientists couldn’t nail down was the exact string of nucleotides to which the microRNAs bound along a messenger RNA transcript.
“To understand exactly how microRNAs work, you want to know their precise targets,” says Darnell, who is a Howard Hughes Medical Institute Investigator and Robert and Harriet Heilbrunn Professor at Rockefeller. “You want a map that tells you which messenger RNAs each microRNA targets and exactly where they are binding.”
The problem was that on any given messenger RNA, there are many sites to which a single microRNA can theoretically bind, and there are hundreds of microRNAs in every cell. Prior techniques -- primarily relying on computer predictions -- weren’t very good at sorting through the morass of predictions to identify the real sites, explains Darnell. The trick to getting such a map was to freeze a snapshot of microRNAs directly bound to messenger RNA in living cells. Working specifically in mouse brain tissue, that’s what Darnell and his team did using a technique the lab developed called high throughput sequence-crosslinking immunoprecipitation, or HITS-CLIP.
In order to shut down a gene before it is translated, microRNAs must be guided to their target messenger RNAs via a protein called Argonaute. The Argonaute-microRNA-messenger RNA complex now forms a sandwich structure where the microRNA is compressed in the middle. By using their technique to fuse Argonaute to these two RNAs, the team was then able to identify the bound microRNA and its precise target sites across all messenger RNAs expressed in the mouse brain.
The researchers, including first author Sung-Wook Chi, a graduate fellow in Tri-Institutional Computational Biology Program, Julie Zang, a biomedical fellow, and Aldo Mele, a research assistant, found that on average, about two microRNAs bind to each messenger RNA. They also found that microRNAs do not only bind to nucleotides at the terminal end of a messenger RNA, but also at other regions including sequences coding for proteins, and sequences once thought to be “junk RNA,” providing new insights into microRNA biology.
“It is thought that RNA is the molecule that can explain the gap between the complexity of cellular functions and our limited number of genes,” says Darnell. “We now have a platform to evaluate the degree to which microRNAs contribute to this complexity with an extraordinary amount of precision.”
This research was supported in part by the U.S. National Institutes of Health.
Thania Benios | Newswise Science News
Further reports about: > Argonaute > Human Disease > MAP > MicroRNAs > RNA > RNA interactions > RNA interference > Rockefeller > degenerative diseases > genetic information > messenger RNA > molecularly cements proteins > mouse brain > therapeutic treatments > tiny molecules > viral infection > viral infections
Scientists uncover the role of a protein in production & survival of myelin-forming cells
19.07.2018 | Advanced Science Research Center, GC/CUNY
NYSCF researchers develop novel bioengineering technique for personalized bone grafts
18.07.2018 | New York Stem Cell Foundation
A new manufacturing technique uses a process similar to newspaper printing to form smoother and more flexible metals for making ultrafast electronic devices.
The low-cost process, developed by Purdue University researchers, combines tools already used in industry for manufacturing metals on a large scale, but uses...
For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.
To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...
For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.
Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...
Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.
A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...
Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.
"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....
13.07.2018 | Event News
12.07.2018 | Event News
03.07.2018 | Event News
20.07.2018 | Power and Electrical Engineering
20.07.2018 | Information Technology
20.07.2018 | Materials Sciences