E2A expression stimulates Ig hypermutation

Ig hypermutation is limited to a region of 2 kb downstream of the transcription start sites of the Ig loci. The process requires transcription and the presence of Ig enhancer sequences, and is initiated by the activation-induced cytidine deaminase (AID)- mediated deamination of cytidine bases. It remains unknown why AID causes mutations selectively in the Ig genes and not in most other transcribed loci of B cells. In this study, we report that the inactivation of the E2A gene strongly reduces the rate of Ig L chain mutations in the chicken B cell line DT40 without affecting the levels of surface Ig or AID expression. The defect is complemented by the expression of cDNAs corresponding to either of the two E2A splice variants E12 or E47. The results suggest that E2A-encoded proteins enhance Ig hypermutation by recruitment of AID to the Ig loci.