Featured Research

from universities, journals, and other organizations

'Grammar' plays key role in activating genes

Date:
August 12, 2013
Source:
University of California - San Francisco
Summary:
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.

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.


Story Source:

The above story is based on materials provided by University of California - San Francisco. Note: Materials may be edited for content and length.


Journal Reference:

  1. Robin P Smith, Leila Taher, Rupali P Patwardhan, Mee J Kim, Fumitaka Inoue, Jay Shendure, Ivan Ovcharenko, Nadav Ahituv. Massively parallel decoding of mammalian regulatory sequences supports a flexible organizational model. Nature Genetics, 2013; DOI: 10.1038/ng.2713

Cite This Page:

University of California - San Francisco. "'Grammar' plays key role in activating genes." ScienceDaily. ScienceDaily, 12 August 2013. <www.sciencedaily.com/releases/2013/08/130812170336.htm>.
University of California - San Francisco. (2013, August 12). 'Grammar' plays key role in activating genes. ScienceDaily. Retrieved September 21, 2014 from www.sciencedaily.com/releases/2013/08/130812170336.htm
University of California - San Francisco. "'Grammar' plays key role in activating genes." ScienceDaily. www.sciencedaily.com/releases/2013/08/130812170336.htm (accessed September 21, 2014).

Share This



More Health & Medicine News

Sunday, September 21, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Sierra Leone's Nationwide Ebola Curfew Underway

Sierra Leone's Nationwide Ebola Curfew Underway

Newsy (Sep. 20, 2014) Sierra Leone is locked down as aid workers and volunteers look for new cases of Ebola. Video provided by Newsy
Powered by NewsLook.com
Changes Found In Brain After One Dose Of Antidepressants

Changes Found In Brain After One Dose Of Antidepressants

Newsy (Sep. 19, 2014) A study suggest antidepressants can kick in much sooner than previously thought. Video provided by Newsy
Powered by NewsLook.com
Could Grief Affect The Immune Systems Of Senior Citizens?

Could Grief Affect The Immune Systems Of Senior Citizens?

Newsy (Sep. 19, 2014) The study found elderly people are much more likely to become susceptible to infection than younger adults going though a similar situation. Video provided by Newsy
Powered by NewsLook.com
Jury Delivers Verdict in Salmonella Trial

Jury Delivers Verdict in Salmonella Trial

AP (Sep. 19, 2014) A federal jury has convicted three people in connection with an outbreak of salmonella poisoning five years ago that sickened hundreds of people and was linked to a number of deaths. (Sept. 19) Video provided by AP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins