Featured Research

from universities, journals, and other organizations

Enhancers serve to restrict potentially dangerous hypermutation to antibody genes

Date:
April 1, 2014
Source:
PLOS
Summary:
How B lymphocytes are able to direct mutations to their antibody genes to produce millions of different antibodies has fascinated biologists for decades. A new study shows that this process of programmed, spatially targeted genome mutation is controlled by nearby transcription regulatory sequences called enhancers. These antibody enhancers are now shown to act in marking the antibody genes as sites of hypermutation. This work illustrates how undesirable off-target effects of hypermutation can be spatially restrained.

How B lymphocytes are able to direct mutations to their antibody genes to produce millions of different antibodies has fascinated biologists for decades. A new study publishing in the Open Access journal PLOS Biology on April 1 by Buerstedde and colleagues shows that this process of programmed, spatially targeted genome mutation (aka. somatic hypermutation) is controlled by nearby transcription regulatory sequences called enhancers. Enhancers are usually known to control gene transcription, and these antibody enhancers are now shown to also act in marking the antibody genes as sites of hypermutation. This work illustrates how undesirable off-target effects of hypermutation can be spatially restrained.

Studies in the late eighties by the laboratories of two prominent immunologists, Ursula Storb and Michael Neuberger, provided some early evidence that the hypermutation process was targeted by sequences neighbouring antibody genes. However, the phenomenon could not be nailed down, because the experimental set-up was laborious and hampered by background noise. Further confounding this analysis was the fact these sequences correspond to enhancers, and enhancers regulate transcription, which happens to be another requirement for hypermutation. To overcome these hurdles, Buerstedde and colleagues developed a novel, highly sensitive, and carefully controlled assay with which they finally provide convincing evidence that enhancers play an important role in somatic hypermutation. The authors are particularly gratified that the new results vindicate earlier pioneering work, and thus resolve the often confusing scientific literature on this topic.

The experimental advantages of a chicken B cell line termed DT40 turned out to be the key to success. This is a little ironic as the DT40 model system has often been criticized for being artificial and of limited relevance for mice and man. However, human enhancers to antibody genes actually increased hypermutation in DT40 cells even more than equivalent sequences from chicken antibody genes. This works demonstrates once more the power of simple experimental models as well as the clear conservation of the targeting mechanism from chicken to humans.

While the study provides an unambiguous resolution of a long-standing question, more work on the precise molecular mechanism is required. Follow-up studies should focus on the interaction of enhancers, gene transcriptional machinery and AID (Activation-Induced Deaminase), the enzyme that initiates hypermutation. With respect to human disease it will be equally important to understand why the mutation targeting mechanism is not fool proof and why AID increases the background mutation rate throughout the genome of B lymphocytes leading to leukemia and lymphomas. It might be possible to use gene targeting to produce lethal mutations in precancerous AID expressing cells.


Story Source:

The above story is based on materials provided by PLOS. Note: Materials may be edited for content and length.


Journal Reference:

  1. Jean-Marie Buerstedde, Jukka Alinikula, Hiroshi Arakawa, Jessica J. McDonald, David G. Schatz. Targeting Of Somatic Hypermutation By immunoglobulin Enhancer And Enhancer-Like Sequences. PLoS Biology, 2014; 12 (4): e1001831 DOI: 10.1371/journal.pbio.1001831

Cite This Page:

PLOS. "Enhancers serve to restrict potentially dangerous hypermutation to antibody genes." ScienceDaily. ScienceDaily, 1 April 2014. <www.sciencedaily.com/releases/2014/04/140401173132.htm>.
PLOS. (2014, April 1). Enhancers serve to restrict potentially dangerous hypermutation to antibody genes. ScienceDaily. Retrieved September 1, 2014 from www.sciencedaily.com/releases/2014/04/140401173132.htm
PLOS. "Enhancers serve to restrict potentially dangerous hypermutation to antibody genes." ScienceDaily. www.sciencedaily.com/releases/2014/04/140401173132.htm (accessed September 1, 2014).

Share This




More Plants & Animals News

Monday, September 1, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

We've Got Mites Living In Our Faces And So Do You

We've Got Mites Living In Our Faces And So Do You

Newsy (Aug. 30, 2014) A new study suggests 100 percent of adult humans (those over 18 years of age) have Demodex mites living in their faces. Video provided by Newsy
Powered by NewsLook.com
Washington Wildlife Center Goes Nuts Over Baby Squirrels

Washington Wildlife Center Goes Nuts Over Baby Squirrels

Reuters - US Online Video (Aug. 30, 2014) An animal rescue in Washington state receives an influx of orphaned squirrels, keeping workers busy as they nurse them back to health. Rough Cut (no reporter narration). Video provided by Reuters
Powered by NewsLook.com
Experimental Ebola Drug ZMapp Cures Lab Monkeys Of Disease

Experimental Ebola Drug ZMapp Cures Lab Monkeys Of Disease

Newsy (Aug. 29, 2014) In a new study, a promising experimental treatment for Ebola managed to cure a group of infected macaque monkeys. Video provided by Newsy
Powered by NewsLook.com
Killer Amoeba Found in Louisiana Water System

Killer Amoeba Found in Louisiana Water System

AP (Aug. 28, 2014) State health officials say testing has confirmed the presence of a killer amoeba in a water system serving three St. John the Baptist Parish towns. (Aug. 28) 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