An assembly of transcription elongation factors known as Super Elongation Complex, or SEC for short, helps paused RNA polymerases to come online and start transcribing the gene ahead, found researchers at the Stowers Institute for Medical Research.
Published in the July 15, 2011, issue of Genes and Development, their study not only assigns a new role to the SEC, but also emphasizes the importance of transcription elongation control for the rapid induction of genes in response to developmental and environmental cues.
“Our findings indicated that SEC facilitates the coordinated and controlled induction of genes that are active during the early developmental stages,” says Ali Shilatifard, Ph.D., investigator and the study’s senior author. “Having preloaded Pol II and general transcription factors reduces the number of steps required for productive transcription and allows cells to respond quickly to internal and external signals.”
Transcriptional control by RNA polymerase II (Pol II) is a tightly orchestrated, multistep process that requires the concerted action of a large number of players to successfully transcribe the full length of genes. For many years, the initiation of transcription—the assembly of the basal transcription machinery at the start site—was considered the rate-limiting step. “We know now that the elongation step is a major node for the regulation of gene expression,” says Shilatifard. “In fact, we have shown that mislocated elongation factors are the cause for pathogenesis of infant acute lymphoblastic and mixed lineage leukemia.”
Mixed lineage leukemia is caused by a chromosomal translocation of the gene named MLL, resulting in its fusion to a seemingly random collection of other genes. Although the translocation partners don’t share any obvious similarities, they all create potent leukemia-causing hybrid genes. In an earlier study, Chengqi Lin, a graduate student in Shilatifard’s lab and first author on the current study, had identified the novel Super Elongation Complex (SEC) as the common denominator shared by all MLL-fusion proteins.
“We found that several frequent translocation partners of MLL are part of a super elongation complex that can activate paused Pol II. The accidental activation of developmentally regulated genes could explain how leukemia arises as a result of MLL translocations,” explains Lin. “However, the function of SEC in our cells is not to give us leukemia, but rather to regulate transcription of developmentally regulated genes, and therefore, we tried to learn more about the normal biological function of SEC.”
They started talking to co-author Robb Krumlauf, the Scientific Director of the Stowers Institute, who has long been interested in Hox genes. Expressed early during development, Hox genes are key regulators of an organism’s basic body plan. Instead of being scattered about the genome randomly they congregate into tight clusters on several chromosomes. A previous collaborative study between Krumlauf’s and Shilatifard’s laboratories demonstrated that Hox gene expression is differentially regulated by MLL. “In light of the functional links between MLL and SEC emerging from Shilatifard’s lab it made sense to study the induction of Hox genes in murine embryonic stem cells, as model system to learn more about SEC and its role during early development,” recalls Krumlauf.
“Hox genes are not only rapidly turned on in differentiating ES cells but because precise regulation of their gene expression is so important to coordinating normal development, they seem to use every known mechanism in the book,” says Krumlauf. “Rather than studying 40 different genes to search for a relevant use of a regulatory mechanism you can often look at the Hox clusters and uncover relevant examples. This makes them a great model system to learn more about the fundamentals of controlling gene expression.”
After initial experiments revealed that SEC is frequently present at highly transcribed regions, Lin in Shilatifard’s lab and Bony De Kumar in Krumlauf’s lab zoomed in on the Hox gene clusters in murine embryonic stem cells. Although both Hoxa1 and Hoxb1 were rapidly induced after treating the cells with retinoic acid, only Hoxa1 was occupied and engaged by paused Pol II. “They are the first genes to be activated within their respective clusters but Hoxa1 is a little bit faster than Hoxb1,” Krumlauf’s says, “which Lin showed is likely the result of the presence of preloaded Pol II on Hoxa1.”
When he expanded his analysis to the whole genome, Lin was able to identify a set of rapidly induced genes that contain paused Pol II. Many of them also recruit SEC in a fairly synchronous and uniform manner to the treatment with retinoic acid, which signals embryonic stem cells to turn on early developmental genes.
One notable exception among the first responders was the gene Cyp26a1, which encodes a cytochrome P450 that metabolizes retinoic acid and is essential for development. Although it lacks preloaded Pol II it is rapidly induced and still needed SEC for its rapid activation. “Not only did it come up extremely fast but it was also induced to much higher levels than the other very early retinoic acid-induced genes containing Pol II,” observed Lin.
“Paused Pol II may not be strictly necessary for rapid induction, but rather facilitate coordinated and controlled induction,” says Shilatifard. “Having preloaded Pol II and general transcription factors reduces the number of steps required for productive transcription and could result in a more equivalent and uniform way to induce gene expression.”
Researchers who also contributed to the work include Alexander S. Garrett, Edwin R. Smith, Madelaine Gogol and Christopher Seidel.
This study was supported National Institutes of Health, and the National Cancer Institute grants R01CA89455, R01CA150265, Alex’s Lemonade Stand Foundation for Childhood Cancer grant and generous funding from the Stowers Institute for Medical Research.
About the Stowers Institute for Medical Research
The Stowers Institute for Medical Research is a non-profit, basic biomedical research organization dedicated to improving human health by studying the fundamental processes of life. Jim Stowers, founder of American Century Investments, and his wife Virginia opened the Institute in 2000. Since then, the Institute has spent over a half billion dollars in pursuit of its mission.
Currently the Institute is home to nearly 500 researchers and support personnel; over 20 independent research programs; and more than a dozen technology development and core facilities. Learn more about the Institute at http://www.stowers.org. Learn more about American Century Investments at http://www.americancentury.com.
Gina Kirchweger | Newswise Science News
Don't Give the Slightest Chance to Toxic Elements in Medicinal Products
23.03.2018 | Physikalisch-Technische Bundesanstalt (PTB)
North and South Cooperation to Combat Tuberculosis
22.03.2018 | Universität Zürich
Satellites in near-Earth orbit are at risk due to the steady increase in space debris. But their mission in the areas of telecommunications, navigation or weather forecasts is essential for society. Fraunhofer FHR therefore develops radar-based systems which allow the detection, tracking and cataloging of even the smallest particles of debris. Satellite operators who have access to our data are in a better position to plan evasive maneuvers and prevent destructive collisions. From April, 25-29 2018, Fraunhofer FHR and its partners will exhibit the complementary radar systems TIRA and GESTRA as well as the latest radar techniques for space observation across three stands at the ILA Berlin.
The "traffic situation" in space is very tense: the Earth is currently being orbited not only by countless satellites but also by a large volume of space...
An international team of researchers has discovered a new anti-cancer protein. The protein, called LHPP, prevents the uncontrolled proliferation of cancer cells in the liver. The researchers led by Prof. Michael N. Hall from the Biozentrum, University of Basel, report in “Nature” that LHPP can also serve as a biomarker for the diagnosis and prognosis of liver cancer.
The incidence of liver cancer, also known as hepatocellular carcinoma, is steadily increasing. In the last twenty years, the number of cases has almost doubled...
In just a few weeks from now, the Chinese space station Tiangong-1 will re-enter the Earth's atmosphere where it will to a large extent burn up. It is possible that some debris will reach the Earth's surface. Tiangong-1 is orbiting the Earth uncontrolled at a speed of approx. 29,000 km/h.Currently the prognosis relating to the time of impact currently lies within a window of several days. The scientists at Fraunhofer FHR have already been monitoring Tiangong-1 for a number of weeks with their TIRA system, one of the most powerful space observation radars in the world, with a view to supporting the German Space Situational Awareness Center and the ESA with their re-entry forecasts.
Following the loss of radio contact with Tiangong-1 in 2016 and due to the low orbital height, it is now inevitable that the Chinese space station will...
Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP, provider of research and development services for OLED lighting solutions, announces the founding of the “OLED Licht Forum” and presents latest OLED design and lighting solutions during light+building, from March 18th – 23rd, 2018 in Frankfurt a.M./Germany, at booth no. F91 in Hall 4.0.
They are united in their passion for OLED (organic light emitting diodes) lighting with all of its unique facets and application possibilities. Thus experts in...
A new scenario seeking to explain how Mars' putative oceans came and went over the last 4 billion years implies that the oceans formed several hundred million...
23.03.2018 | Event News
19.03.2018 | Event News
16.03.2018 | Event News
23.03.2018 | Materials Sciences
23.03.2018 | Agricultural and Forestry Science
23.03.2018 | Physics and Astronomy