(Press-News.org) 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 programed, 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.
INFORMATION:
Please mention PLOS Biology as the source for this article and include the links below in your coverage to take readers to the online, open access articles
All works published in PLOS Biology are open access, which means that everything is immediately and freely available. Use this URL in your coverage to provide readers access to the paper upon publication:
http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1001831
Contact:
Jean-Marie Buerstedde
Centre for Chromosome Stability
National University of Ireland, Galway (NUIGalway)
Department of Biochemistry
University Road, Galway, Ireland
Email: brstdd@gmail.com
Phone: 00353 89 448 4112
Citation: Buerstedde J-M, Alinikula J, Arakawa H, McDonald JJ, Schatz DG (2014) Targeting of Somatic Hypermutation by immunoglobulin Enhancer and Enhancer-Like Sequences. PLoS Biol 12(4): e1001831. doi:10.1371/journal.pbio.1001831
Funding: J-M.B. was supported by an International Outgoing Marie Curie Fellowship. J.J.M. was supported in part by NIH T32 AI07019. D.G.S is an investigator of the Howard Hughes Medical Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
Enhancers serve to restrict potentially dangerous hypermutation to antibody genes
2014-04-02
ELSE PRESS RELEASES FROM THIS DATE:
Going batty for jumping DNA as a cause of species diversity
2014-04-02
The vesper bats are the largest and best-known common family of bats, with more than 400 species spread across the globe, ranking second among mammals in species diversity.
Authors Ray et al., wanted to get at the root cause of this diversity by taking advantage of two vesper bat species whose genomes have recently been sequenced. They speculated that one cause of this diversity might be jumping elements in the genome, called DNA transposons, which are more active and recent in the evolutionary history of this family than any other mammal. Why and how this DNA transposon ...
Likely culprit in spread of colon cancer identified
2014-04-02
New research at Washington University School of Medicine in St. Louis and Vanderbilt University Medical Center in Nashville has implicated a poorly understood protein called PLAC8 in the spread of colon cancer.
While elevated PLAC8 levels were known to be associated with colon cancer, the researchers now have shown that the protein plays an active role in shifting normal cells lining the colon into a state that encourages metastasis.
The work appears April 1 in the Journal of Clinical Investigation.
"We knew levels of this protein are elevated in colon cancer," said ...
Gene therapy improves limb function following spinal cord injury
2014-04-02
Delivering a single injection of a scar-busting gene therapy to the spinal cord of rats following injury promotes the survival of nerve cells and improves hind limb function within weeks, according to a study published April 2 in The Journal of Neuroscience. The findings suggest that, with more confirming research in animals and humans, gene therapy may hold the potential to one day treat people with spinal cord injuries.
The spinal cord is the main channel through which information passes between the brain and the rest of the body. Most spinal cord injuries are caused ...
Mode of action of new multiple sclerosis drug discovered
2014-04-02
This news release is available in German. Just a few short weeks ago, dimethyl fumarate was approved in Europe as a basic therapy for multiple sclerosis. Although its efficacy has been established in clinical studies, its underlying mode of action was still unknown, but scientists from Bad Nauheim's Max Planck Institute for Heart and Lung Research and the University of Lübeck have now managed to decode it. They hope that this knowledge will help them develop more effective therapeutic agents.
Multiple sclerosis (MS) is a chronic inflammatory disease of the central ...
Well-rested flies
2014-04-02
This news release is available in German. Elderly flies do not sleep well – they frequently wake up during the night and wander around restlessly. The same is true of humans. For researchers at the Max Planck Institute for Biology of Ageing in Cologne, the sleeplessness experienced by the fruit fly Drosophila is therefore a model case for human sleeping behaviour. The scientists have now discovered molecules in the flies' cells that affect how the animals sleep in old age: if insulin/IGF signalling is active, the quality of the animals' sleep is reduced and they wake ...
Penn Medicine points to new ways to prevent relapse in cocaine-addicted patients
2014-04-02
(PHILADELPHIA) – Relapse is the most painful and expensive feature of drug addiction—even after addicted individuals have been drug-free for months or years, the likelihood of sliding back into the habit remains high. The National Institute on Drug Abuse estimates that 40 to 60 percent of addicted individuals will relapse, and in some studies the rates are as high as 80 percent at six months after treatment. Though some relapse triggers can be consciously avoided, such as people, places and things related to drug use, other subconscious triggers related to the brain's reward ...
The mammography dilemma
2014-04-01
A comprehensive review of 50 year's worth of international studies assessing the benefits and harms of mammography screening suggests that the benefits of the screening are often overestimated, while harms are underestimated. And, since the relative benefits and harms of screening are related to a complex array of clinical factors and personal preferences, physicians and patients need more guidance on how best to individualize their approach to breast cancer screening.
The results of the review by researchers at Harvard Medical School's Department of Health Care Policy ...
Overuse of blood transfusions increases infection risk
2014-04-01
ANN ARBOR, Mich. — Blood transfusions are one of the most common procedures patients receive in the hospital but the more red blood cells they receive, the greater their risk of infection, says a new study led by the University of Michigan Heath System and VA Ann Arbor Healthcare System.
Researchers analyzed 21 randomized controlled trials for the study that appears in today's Journal of the American Medical Association (JAMA).
Elderly patients undergoing hip or knee surgeries were most susceptible, with a 30 percent lower risk of infection when fewer transfusions ...
Medication does not help prevent ED following radiation therapy for prostate cancer
2014-04-01
Among men undergoing radiation therapy for prostate cancer, daily use of the erectile dysfunction drug tadalafil, compared with placebo, did not prevent loss of erectile function, according to a study in the April 2 issue of JAMA.
Erectile dysfunction (ED) is a common condition resulting from many causes, including prostate cancer treatment. An estimated 40 percent of men report ED after radiation therapy, and half of all men use erectile aids following this therapy. Tadalafil is used to treat erectile dysfunction after prostate cancer treatment, but its role as a preventive ...
Outcomes of administering blood transfusions to patients with lower levels of hemoglobin
2014-04-01
Restricting red blood cell (RBC) transfusions among hospitalized patients to those with hemoglobin (the iron-containing protein in RBCs) measures below a certain level is associated with a lower risk of health care-associated infections, according to a study in the April 2 issue of JAMA.
Efforts to prevent health care-associated infection are among the priorities for the U.S. Department of Health and Human Services. The estimated annual direct medical costs of health care-associated infections to U.S. hospitals ranges from $28 billion to $45 billion, with about 1 in ...