Targeting of Somatic Hypermutation By immunoglobulin Enhancer and Enhancer-Like Sequences

Somatic hypermutation (sh) generates point mutations within rearranged immunoglobulin (ig) genes of activated b cells,providing genetic diversity for the affinity maturation of antibodies. sh requires the activation-induced cytidine deaminase (aid) protein and transcription of the mutation target sequence,but how the ig gene specificity of mutations is achieved has remained elusive. we show here using a sensitive and carefully controlled assay that the ig enhancers strongly activate sh in neighboring genes even though their stimulation of transcription is negligible. mutations in certain e-box,nfκb,mef2,or ets family binding sites-known to be important for the transcriptional role of ig enhancers-impair or abolish the activity. full activation of sh typically requires a combination of multiple ig enhancer and enhancer-like elements. the mechanism is evolutionarily conserved,as mammalian ig lambda and ig heavy chain intron enhancers efficiently stimulate hypermutation in chicken cells. our results demonstrate a novel regulatory function for ig enhancers,indicating that they either recruit aid or alter the accessibility of the nearby transcription units. © 2014 buerstedde et al.