Long segments of RNA— encoded in our DNA but not translated into protein—are key to physically manipulating DNA in order to activate certain genes, say researchers at The Wistar Institute. These non-coding RNA-activators (ncRNA-a) have a crucial role in turning genes on and off during early embryonic development, researchers say, and have also been connected with diseases, including some cancers, in adults.
In an online article of the journal Nature, a team of scientists led by Wistar's Ramin Shiekhattar, Ph.D., detail the mechanism by which long non-coding RNA-activators promote gene expression. They show how these RNA molecules help proteins in the cell to create a loop of DNA in order to open up genes for transcription. Their experiments have also described how particular ncRNA-a molecules are related to FG syndrome, a genetic disease linked to severe neurological and physical deficits. "These ncRNA-activators can activate specific genes by working with large protein complexes, filling in a big piece of the puzzle," said Shiekhattar, Herbert Kean, M.D., Family Professor and senior author of the study. "Our DNA encodes thousands of these ncRNA-activators, each with a role in timing the expression of a specific gene. As we learn more about non-coding RNA, I believe we will have a profoundly better understanding of how our genes function."
Their findings also provide a plausible mechanism of how locations along chromosomes, classically known as "enhancer" elements, can influence the expression ("reading") of genes located 5,000 to 100,000 base pairs ("letters") of DNA away. According to their findings, ncRNA-a molecules bind to large protein complexes to form a loop of DNA, which then opens up the gene to the molecular machinery that transcribes DNA. "There is an abundance of evidence to indicate that enhancers are critical components of transcription during embryonic development and disease process," Shiekhattar said.
Mutations in the MED12 protein are a marker for FG syndrome (also know as Opitz–Kaveggia syndrome), a rare genetic disorder that leads to abnormalities throughout the body and varying degrees of physical and neurological problems. "This clearly shows how activating ncRNAs can influence disease development, an idea that has been gaining evidence in the scientific literature," Shiekhattar said. To confirm that ncRNA-a works with Mediator to form a loop in DNA, the researchers used a technique called chromosome conformation capture (3C) to gain a better understanding of the three-dimensional structure of chromosomes. Their results show how Mediator gets a foothold of sorts on the portion of DNA that encodes the ncRNA-a, and twists the DNA to form a loop.
"The looping mechanism serves to physically bring together a distant enhancer element with the start site of the targeted gene, allowing Mediator to recruit the proteins responsible for reading the gene to the location," Shiekhattar said. "It is at least one answer to how these classical enhancer elements function while being physically distant from their target genes."
The Shiekhattar laboratory is supported by grants from the National Institutes of Health (P30 CA 010815).
Wistar co-authors include Fan Lai, Ph.D., lead author, and Matteo Cesaroni, Ph.D., postdoctoral fellows in the Shiekhattar laboratory. Co-authors include Ulf Andersson Ørom, Ph.D., Max Planck Institute for Molecular Genetics; Malte Beringer, Ph.D., Center de Regulacio Genomica, Barcelona; Dylan J. Taatjes, Ph.D., University of Colorado; and Gerd A. Blobel, M.D., Ph.D., The Children's Hospital of Philadelphia.
Greg Lester | EurekAlert!
Multi-institutional collaboration uncovers how molecular machines assemble
02.12.2016 | Salk Institute
Fertilized egg cells trigger and monitor loss of sperm’s epigenetic memory
02.12.2016 | IMBA - Institut für Molekulare Biotechnologie der Österreichischen Akademie der Wissenschaften GmbH
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water
In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...
The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.
Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
02.12.2016 | Medical Engineering
02.12.2016 | Agricultural and Forestry Science
02.12.2016 | Physics and Astronomy