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

More articles from Life Sciences:

nachricht Velcro for human cells
16.01.2019 | Albert-Ludwigs-Universität Freiburg im Breisgau

nachricht More efficient solar cells imitate photosynthesis
16.01.2019 | Friedrich-Alexander-Universität Erlangen-Nürnberg

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Flying Optical Cats for Quantum Communication

Dead and alive at the same time? Researchers at the Max Planck Institute of Quantum Optics have implemented Erwin Schrödinger’s paradoxical gedanken experiment employing an entangled atom-light state.

In 1935 Erwin Schrödinger formulated a thought experiment designed to capture the paradoxical nature of quantum physics. The crucial element of this gedanken...

Im Focus: Nanocellulose for novel implants: Ears from the 3D-printer

Cellulose obtained from wood has amazing material properties. Empa researchers are now equipping the biodegradable material with additional functionalities to produce implants for cartilage diseases using 3D printing.

It all starts with an ear. Empa researcher Michael Hausmann removes the object shaped like a human ear from the 3D printer and explains:

Im Focus: Elucidating the Atomic Mechanism of Superlubricity

The phenomenon of so-called superlubricity is known, but so far the explanation at the atomic level has been missing: for example, how does extremely low friction occur in bearings? Researchers from the Fraunhofer Institutes IWM and IWS jointly deciphered a universal mechanism of superlubricity for certain diamond-like carbon layers in combination with organic lubricants. Based on this knowledge, it is now possible to formulate design rules for supra lubricating layer-lubricant combinations. The results are presented in an article in Nature Communications, volume 10.

One of the most important prerequisites for sustainable and environmentally friendly mobility is minimizing friction. Research and industry have been dedicated...

Im Focus: Mission completed – EU partners successfully test new technologies for space robots in Morocco

Just in time for Christmas, a Mars-analogue mission in Morocco, coordinated by the Robotics Innovation Center of the German Research Center for Artificial Intelligence (DFKI) as part of the SRC project FACILITATORS, has been successfully completed. SRC, the Strategic Research Cluster on Space Robotics Technologies, is a program of the European Union to support research and development in space technologies. From mid-November to mid-December 2018, a team of more than 30 scientists from 11 countries tested technologies for future exploration of Mars and Moon in the desert of the Maghreb state.

Close to the border with Algeria, the Erfoud region in Morocco – known to tourists for its impressive sand dunes – offered ideal conditions for the four-week...

Im Focus: Programming light on a chip

Research opens doors in photonic quantum information processing, optical signal processing and microwave photonics

Researchers from the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) have developed a new integrated photonics platform that can...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Our digital society in 2040

16.01.2019 | Event News

11th International Symposium: “Advanced Battery Power – Kraftwerk Batterie” Aachen, 3-4 April 2019

14.01.2019 | Event News

ICTM Conference 2019: Digitization emerges as an engineering trend for turbomachinery construction

12.12.2018 | Event News

 
Latest News

Velcro for human cells

16.01.2019 | Life Sciences

Kiel physicists discover new effect in the interaction of plasmas with solids

16.01.2019 | Physics and Astronomy

The pace at which the world’s permafrost soils are warming

16.01.2019 | Earth Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>