Induction of somatic hypermutation is associated with modifications in immunoglobulin variable region chromatin

Somatic hypermutation (SHM) requires selective targeting of the mutational machinery to the variable region of the immunoglobulin heavy chain gene. The induction of SHM in the BL2 cell line upon costimulation is associated with hyperacetylation of the chromatin at the variable region but not at the constant region. The V region-restricted histone hyperacetylation resulting from costimulation occurs independent of AID expression and mutation. Interestingly, costimulation in the presence of Trichostatin A causes hyperacetylation of histones associated with the constant region and extends mutations to the constant region. Under this condition, promoter proximal mutations are observed in the variable region as well. The overexpression of AID results in a similar deregulation of mutational targeting. Our results indicate that the stimulation of SHM in BL2 cells activates two independent pathways resulting in histone modifications that permit induced levels of AID to selectively target the variable region for mutation.