Targeting of somatic hypermutation by immunoglobulin enhancer and enhancer-like sequences.

• Main Authors: Jean-Marie Buerstedde, Jukka Alinikula, Hiroshi Arakawa, Jessica J McDonald, David G Schatz
• Format: Article
• Language: English
• Published: Public Library of Science (PLoS) 2014-04-01
• Series: PLoS Biology
• Online Access: https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24691034/?tool=EBI

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.