Allelic 'choice' governs somatic hypermutation in vivo at the immunoglobulin kappa-chain locus.
Monoallelic demethylation and rearrangement control allelic exclusion of the immunoglobulin kappa-chain locus (Igk locus) in B cells. Here, through the introduction of pre-rearranged Igk genes into their physiological position, the critical rearrangement step was bypassed, thereby generating mice producing B cells simultaneously expressing two different immunoglobulin-kappa light chains. Such 'double-expressing' B cells still underwent monoallelic demethylation at the Igk locus, and the demethylated allele was the 'preferred' substrate for somatic hypermutation in each cell. However, methylation itself did not directly inhibit the activation-induced cytidine-deaminase reaction in vitro. Thus, it seems that the epigenetic mechanisms that initially bring about monoallelic variable-(diversity)-joining rearrangement continue to be involved in the control of antibody diversity at later stages of B cell development.
Fraenkel
Shira
S
The Hebrew University Hadassah Medical School, Jerusalem 91120, Israel.
Mostoslavsky
Raul
R
Novobrantseva
Tatiana I
TI
Pelanda
Roberta
R
Chaudhuri
Jayanta
J
Esposito
Gloria
G
Jung
Steffen
S
Alt
Frederick W
FW
Rajewsky
Klaus
K
Cedar
Howard
H
Bergman
Yehudit
Y
D000483:Alleles; D000818:Animals; D000916:Antibody Diversity / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000276:immunology; D015322:Gene Rearrangement, B-Lymphocyte; D005819:Genetic Markers; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000096:biosynthesis / Q000235:genetics; D007145:Immunoglobulin kappa-Chains / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D027041:Somatic Hypermutation, Immunoglobulin
D005819:Genetic Markers; D007135:Immunoglobulin Variable Region; D007145:Immunoglobulin kappa-Chains