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 ImmunologyJournal information
Saeko Okada | Research asia research news
First time-lapse footage of cell activity during limb regeneration
25.10.2016 | eLife
Phenotype at the push of a button
25.10.2016 | Institut für Pflanzenbiochemie
Ultrafast lasers have introduced new possibilities in engraving ultrafine structures, and scientists are now also investigating how to use them to etch microstructures into thin glass. There are possible applications in analytics (lab on a chip) and especially in electronics and the consumer sector, where great interest has been shown.
This new method was born of a surprising phenomenon: irradiating glass in a particular way with an ultrafast laser has the effect of making the glass up to a...
Terahertz excitation of selected crystal vibrations leads to an effective magnetic field that drives coherent spin motion
Controlling functional properties by light is one of the grand goals in modern condensed matter physics and materials science. A new study now demonstrates how...
Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.
"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...
In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.
A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...
By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.
"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...
14.10.2016 | Event News
14.10.2016 | Event News
12.10.2016 | Event News
26.10.2016 | Physics and Astronomy
26.10.2016 | Earth Sciences
25.10.2016 | Earth Sciences