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.
Woo
Caroline J
CJ
Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Chanin 403, Bronx, NY 10461, USA.
Martin
Alberto
A
Scharff
Matthew D
MD
D000107:Acetylation; D000818:Animals; D002843:Chromatin / Q000502:physiology*; D005803:Genes, Immunoglobulin; D006657:Histones / Q000378:metabolism; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D051379:Mice; D011233:Precipitin Tests; D027041:Somatic Hypermutation, Immunoglobulin
D002843:Chromatin; D006657:Histones; D007135:Immunoglobulin Variable Region; C468783:H2AX protein, human; C475961:gamma-H2AX protein, mouse