Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers find 'grammar' plays key role in activating genes

13.08.2013
Insight from UCSF-led study may advance gene and cell therapy

Researchers have probed deep into the cell’s genome, beyond the basic genetic code, to begin learning the “grammar” that helps determine whether or not a gene gets switched on to make the protein it encodes.

Their discovery -- that the ordering of specific DNA sequences in key regions of the genome affects the activity of genes -- might advance efforts to use gene and cell-based therapies to treat disease, said UCSF molecular biologist Nadav Ahituv, PhD, senior scientist on the study. The findings were published online in the journal Nature Genetics on July 28 and will appear in the September print edition.

In gene therapy, which is still experimental, specific genes are delivered to cells to make proteins that improve cellular physiology and fight disease. The new findings offer a way to activate these genes in specific tissues.

“Our work suggests a framework for the design of synthetic, tissue-specific DNA that could be used to control gene activation,” said Ahituv, an associate professor in the UCSF School of Pharmacy.

An individual’s genes are essentially the same in every cell. However, different combinations of genes are either silent or actively making protein in different cells. These patterns of gene activation make the lips differ from the liver, for instance, and determine whether the liver is functioning normally or not.

In their new study, Ahituv and colleagues made significant progress in understanding the integration of information and decision-making that goes on within the DNA regions that guide this gene activation.

The researchers determined that key bits of DNA, called “enhancers,” which serve as a type of gene regulator, do not operate in an all-or-nothing manner to control whether or not genes are active. Instead, the researchers found that changes in the arrangements of specific DNA sequences within these enhancers result in changes in levels of gene activity, similar to the way changing the syntax of a sentence affects its meaning.

Enhancers, when bound by proteins called transcription factors, play a necessary role in activating specific genes that may be quite a distance away within the cell’s chromosomes. The arrangement of DNA sequences in the enhancers determines the likelihood that matching transcription factors found in specific cell types will attach and cause the activation of genes, the scientists discovered.

The findings point to a strategy for designing DNA enhancers that might optimally guide gene activity in specific tissues targeted for gene therapy. Similar strategies might be used to help guide the development of cell therapies from stem cells for use in regenerative medicine to replace damaged tissue, according to Ahituv.

Like more than 98 percent of DNA in the human genome, enhancers lie outside genes, and are referred to as “non-coding.” Mutations in enhancers already have been implicated in human limb malformations, deafness, skeletal abnormalities, other birth defects and cancer, Ahituv said. Additional enhancer mutations may prove to be responsible for many associations between DNA variations and diseases that have been identified in genome-spanning probes to compare people with and without specific diseases, he said.

Working with mice and with human liver-cancer cells grown in the lab, the researchers relied on a powerful new lab technique in order to be able to perform what they describe as a “massively parallel experiment” to explore roles that specific combinations of enhancers play in guiding gene activation.

They designed a diverse library of nearly 5,000 enhancers, consisting of transcription-factor binding sites from 12 known liver-specific transcription factors, and placed each into a DNA package that could be injected into a mouse’s tail, move into it’s liver, and potentially be activated by transcription factors in the mouse’s liver cells. With this technique they were able to measure the ability of each enhancer to interact with liver transcription factors to turn on genes.

A technology developed recently in the laboratory of co-author Jay Shendure, PhD, from the University of Washington, allowed the research team to rapidly obtain a unique read-out — like a genetic bar code — each time one of the enhancers was involved in gene activation.

Leila Taher, PhD, and Ivan Ovcharenko, PhD, of the National Center for Biotechnology Information, part of the National Library of Medicine, also contributed to the study by developing algorithms used to design the synthetic enhancers and to analyze the large amounts of data gathered.

The genetic code was cracked a half-century ago. It specifies how DNA’s four nucleic acid, alphabet-building blocks — A, C, T, and G — encode protein. As cellular machinery reads through a gene’s long DNA sequences, sequential three-letter combinations of these nucleic acids, called codons, specify which amino acids will in turn be linked together to make the gene-encoded protein.

But molecular biologists have been slower to unravel the mysteries of development as it unfolds through cell division and maturation through different patterns of gene activation, and slower to understand the role of DNA outside of genes.

Additional authors of the Nature Genetics study include postdoctoral fellows Robin Smith, PhD, and Fumitaka Inoue, PhD, and graduate student Mee Kim from UCSF; and Rupali Patwardhan, a graduate student from the University of Washington. The research was funded by the National Institutes of Health, including major funding from the National Human Genome Research Institute, and by the UCSF Liver Center.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.

Jeffrey Norris | EurekAlert!
Further information:
http://www.ucsf.edu

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Making lightweight construction suitable for series production

More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.

Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...

Im Focus: Wonder material? Novel nanotube structure strengthens thin films for flexible electronics

Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.

"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

7th International Conference on Crystalline Silicon Photovoltaics in Freiburg on April 3-5, 2017

03.04.2017 | Event News

 
Latest News

DGIST develops 20 times faster biosensor

24.04.2017 | Physics and Astronomy

Nanoimprinted hyperlens array: Paving the way for practical super-resolution imaging

24.04.2017 | Materials Sciences

Atomic-level motion may drive bacteria's ability to evade immune system defenses

24.04.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>