Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Finding the right combination

22.02.2010
A combination of positive and negative regulation narrowly restricts a genome-shuffling enzyme’s activity

Diversity may be the spice of life, but it’s also the key to an effective immune system, as B lymphocytes rely on extensive recombination to shuffle their antibody-coding genes to produce molecules that can recognize a diverse array of potential threats.

Antibodies with established targets can also undergo further alterations to modulate the immune response that they trigger upon antigen binding. Known as ‘class switch recombination’ (CSR), this process relies on activation-induced cytidine deaminase (AID), an enzyme that induces major rearrangements in antibody-coding loci.

Unregulated, AID can generate cancer-causing genomic rearrangements, and a team led by Tasuku Honjo and Hitoshi Nagaoka at the University of Kyoto, with Sidonia Fagarasan’s group at the RIKEN Research Center for Allergy and Immunology in Yokohama, recently set about exploring the mechanisms that help constrain expression of the Aicda gene.

“AID is tightly regulated in activated B cells and speculated to be a B cell-specific factor—however, the Aicda promoter is not lymphocyte specific,” says Thinh Huy Tran, lead author of the team’s recent article in Nature Immunology1. Comparison of the mouse and human versions of this promoter revealed four discrete segments that had been closely conserved throughout evolution. To assess their contributions to gene specificity, the researchers generated artificial promoters consisting of various subsets of these conserved regions, which they used to regulate a bioluminescence-producing ‘reporter’ gene in cultured lymphocytes.

They found that two of these four segments directly contribute to specificity. ‘Region 2’ contains binding sites for transcription factors known to guide B lymphocyte development, but also contains sequences that strongly inhibit Aicda expression. The other promoter segment, ‘region 4’, appears to participate in the strong induction of this gene in response to signaling factors that trigger CSR in vivo.

“Our results demonstrate for the first time that two separate regions contribute together to regulating Aicda expression, in which silencers are derepressed by B lineage-specific and stimulation-responsive enhancers,” says Tran. “The negative factors that restrict Aicda expression might contribute to retaining genomic stability, while region 4 is essential for Aicda response in B cells to environmental stimulation ... and is critical to generate antibody diversification.”

The investigators are now examining the individual importance of these various putative Aicda regulators, but also intend to further explore the bigger picture of the effects of AID dysregulation. “We plan to investigate the correlation between Aicda expression levels with mutation frequency in non-immune genes ... and the role of AID in tumor development,” says Tran.

The corresponding author for this highlight is based at the Laboratory for Mucosal Immunity, Research Center for Allergy and Immunology

Journal information
1. Tran, T.H., Nakata, M., Suzuki, K., Begum, N.A., Shinkura, R., Fagarasan, S., Honjo, T. & Nagaoka, H. B cell–specific and stimulation-responsive enhancers derepress Aicda by overcoming the effects of silencers. Nature Immunology 11 148-154 (2010).

Saeko Okada | Research asia research news
Further information:
http://www.rikenresearch.riken.jp/eng/research/6182
http://www.researchsea.com

More articles from Life Sciences:

nachricht A Map of the Cell’s Power Station
18.08.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau

nachricht On the way to developing a new active ingredient against chronic infections
18.08.2017 | Deutsches Zentrum für Infektionsforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

A Map of the Cell’s Power Station

18.08.2017 | Life Sciences

Engineering team images tiny quasicrystals as they form

18.08.2017 | Physics and Astronomy

Researchers printed graphene-like materials with inkjet

18.08.2017 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>