Abstract
Ig class switch recombination (CSR) is regulated through long-range intrachromosomal interactions between germline transcript promoters and enhancers to initiate transcription and create chromatin accessible to activation-induced deaminase attack. CSR occurs between switch (S) regions that flank Cmu and downstream C(H) regions and functions via an intrachromosomal deletional event between the donor Smicro region and a downstream S region. It is unclear to what extent S region primary sequence influences differential targeting of CSR to specific isotypes. We address this issue in this study by generating mutant mice in which the endogenous Sgamma3 region was replaced with size-matched Sgamma1 sequence. B cell activation conditions are established that support robust gamma3 and gamma1 germline transcript expression and stimulate IgG1 switching but suppress IgG3 CSR. We found that the Sgamma1 replacement allele engages in micro-->gamma3 CSR, whereas the intact allele is repressed. We conclude that S region identity makes a significant contribution to CSR. We propose that the Sgamma1 region is selectively targeted for CSR following the induction of an isotype-specific factor that targets the S region and recruits CSR machinery.