Immunoglobulin (antibody) genes are the tossed salad of the genome. Unlike other genes (the carefully tended soufflés that retain their integrity through each cell division) multiple segments of immunoglobulin genes from disparate parts of the chromosome mix together multiple times to provide a diverse repertoire of functional antibodies. In two reports in the May issue of Nature Immunology, the DNA sequences that restrict this reshuffling to immunoglobulin genes and their unique structures that provide targets for the recombining enzymes are revealed at last.
Immunoglobulins not only bind to an almost infinite universe of chemicals, but can be converted to different 'classes', so that their efforts to clear toxins and pathogenic organisms synchronize with the overall immune response. This conversion is called 'class switching'. Alt and colleagues at Harvard Medical School in Boston deleted or mutated the 'switching region' of IgG1 genes in mice and measured if the B cells in these mice could still secrete IgG1 into their bloodstreams. In this way the investigators identified stretches of guanine (G) nucleotides as critical targets for the complex enzymes responsible for class switching.
In the paper by Lieber's group at the University of Southern California in Los Angeles, the importance of the G-rich sequence in normal B cells is made clear. Class switching first needs transcription through the switching region; Lieber found this to be necessary because it locally opens up the DNA's double helix, allowing G-rich RNA transcripts access to the C-rich DNA templates, forming temporary RNA*DNA hybrids. The other strand of DNA is the G-rich sequence identified in Alt's studies. Although shoved aside and seemingly useless for transcription, it is now available to serve as a specific target for the class switching machinery.
Together, this pair of elegant studies, looking at a complex, vitally important process in its natural setting, explains how immunoglobulin genes are uniquely identified to switch and why other genes aren't accidentally mangled.
Frederick W. Alt
Dept of Genetics, Harvard Medical School
Boston, MA, USA
Tel: +1 617 355 7290
Michael R. Lieber
Keck School of Medicine
University of Southern California
Los Angeles, CA
Tel: +1 323 865 0568
Additional contact for comment on paper:
David G. Schatz
HHMI Section of Immunobiology
Yale University School of Medicine
New Haven, CT
Tel: +1 203 737 2255
(C) Nature Immunology press release.
Message posted by: Trevor M. D'Souza