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!
Meadows beat out shrubs when it comes to storing carbon
23.11.2017 | Norwegian University of Science and Technology
Migrating Cells: Folds in the cell membrane supply material for necessary blebs
23.11.2017 | Westfälische Wilhelms-Universität Münster
Heat from the friction of rocks caused by tidal forces could be the “engine” for the hydrothermal activity on Saturn's moon Enceladus. This presupposes that...
The WHO reports an estimated 429,000 malaria deaths each year. The disease mostly affects tropical and subtropical regions and in particular the African continent. The Fraunhofer Institute for Silicate Research ISC teamed up with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and the Institute of Tropical Medicine at the University of Tübingen for a new test method to detect malaria parasites in blood. The idea of the research project “NanoFRET” is to develop a highly sensitive and reliable rapid diagnostic test so that patient treatment can begin as early as possible.
Malaria is caused by parasites transmitted by mosquito bite. The most dangerous form of malaria is malaria tropica. Left untreated, it is fatal in most cases....
The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.
Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...
Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.
That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...
Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.
During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....
15.11.2017 | Event News
15.11.2017 | Event News
30.10.2017 | Event News
23.11.2017 | Information Technology
23.11.2017 | Physics and Astronomy
23.11.2017 | Life Sciences