Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Ready, Go!

18.07.2011
Just like orchestra musicians waiting for their cue, RNA polymerase II molecules are poised at the start site of many developmentally controlled genes, waiting for the “Go!”- signal to read their part of the genomic symphony.

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
Further information:
http://www.stowers.org

More articles from Life Sciences:

nachricht Zebrafish's near 360 degree UV-vision knocks stripes off Google Street View
22.06.2018 | University of Sussex

nachricht New cellular pathway helps explain how inflammation leads to artery disease
22.06.2018 | Cedars-Sinai Medical Center

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Temperature-controlled fiber-optic light source with liquid core

In a recent publication in the renowned journal Optica, scientists of Leibniz-Institute of Photonic Technology (Leibniz IPHT) in Jena showed that they can accurately control the optical properties of liquid-core fiber lasers and therefore their spectral band width by temperature and pressure tuning.

Already last year, the researchers provided experimental proof of a new dynamic of hybrid solitons– temporally and spectrally stationary light waves resulting...

Im Focus: Overdosing on Calcium

Nano crystals impact stem cell fate during bone formation

Scientists from the University of Freiburg and the University of Basel identified a master regulator for bone regeneration. Prasad Shastri, Professor of...

Im Focus: AchemAsia 2019 will take place in Shanghai

Moving into its fourth decade, AchemAsia is setting out for new horizons: The International Expo and Innovation Forum for Sustainable Chemical Production will take place from 21-23 May 2019 in Shanghai, China. With an updated event profile, the eleventh edition focusses on topics that are especially relevant for the Chinese process industry, putting a strong emphasis on sustainability and innovation.

Founded in 1989 as a spin-off of ACHEMA to cater to the needs of China’s then developing industry, AchemAsia has since grown into a platform where the latest...

Im Focus: First real-time test of Li-Fi utilization for the industrial Internet of Things

The BMBF-funded OWICELLS project was successfully completed with a final presentation at the BMW plant in Munich. The presentation demonstrated a Li-Fi communication with a mobile robot, while the robot carried out usual production processes (welding, moving and testing parts) in a 5x5m² production cell. The robust, optical wireless transmission is based on spatial diversity; in other words, data is sent and received simultaneously by several LEDs and several photodiodes. The system can transmit data at more than 100 Mbit/s and five milliseconds latency.

Modern production technologies in the automobile industry must become more flexible in order to fulfil individual customer requirements.

Im Focus: Sharp images with flexible fibers

An international team of scientists has discovered a new way to transfer image information through multimodal fibers with almost no distortion - even if the fiber is bent. The results of the study, to which scientist from the Leibniz-Institute of Photonic Technology Jena (Leibniz IPHT) contributed, were published on 6thJune in the highly-cited journal Physical Review Letters.

Endoscopes allow doctors to see into a patient’s body like through a keyhole. Typically, the images are transmitted via a bundle of several hundreds of optical...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Munich conference on asteroid detection, tracking and defense

13.06.2018 | Event News

2nd International Baltic Earth Conference in Denmark: “The Baltic Sea region in Transition”

08.06.2018 | Event News

ISEKI_Food 2018: Conference with Holistic View of Food Production

05.06.2018 | Event News

 
Latest News

Graphene assembled film shows higher thermal conductivity than graphite film

22.06.2018 | Materials Sciences

Fast rising bedrock below West Antarctica reveals an extremely fluid Earth mantle

22.06.2018 | Earth Sciences

Zebrafish's near 360 degree UV-vision knocks stripes off Google Street View

22.06.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>