Targeting of Aid-Mediated Immunoglobulin Gene Diversification by Mutation Enhancer Elements

Project: National Science and Technology CouncilNational Science and Technology Council Academic Grants

Project Details


Efficient humoral immune responses rely on the generation of high-affinity antibodies by a process called affinity maturation. This involves an iterative mechanism in which somatic hypermutation (SHM) and/or immunoglobulin gene conversion (GCV) generate random point mutations in immunoglobulin (Ig) genes, and a subsequent selection step ensures the survival of cells encoding high affinity antibodies. SHM and GCV are both initiated by activation-induced cytidine deaminase (AID) creating U:G mismatches that are subsequently fixed by mutagenic repair pathways. How these mutagenic activities are focused selectively on Ig genes had been the topic of intense research efforts for more than a decade. We recently discovered that SHM/GCV activity is focused to Ig loci by cis-regulatory DNA sequences named targeting elements. Using chicken DT40 cells as our model system we showed that these elements are distinct from classical transcriptional enhancers, and hence named them mutation enhancer elements (MEEs). This proposal is now aimed at understanding a fundamental question in the field: how do these MEEs function? We will focus on one specific element, the 3′MEE in the chicken IGL locus, and try to (1) identify the trans-acting factors that bind to it, their binding sites, and (2) determine whether this elements recruits AID activity or induces error-prone DNA repair. Furthermore, we will expand our work to human and mouse Ig genes and identify the MEEs in these loci. Combined our proposed studies will provide knowledge that is critical for understanding the role of these MEEs in human health and disease, and start to reveal the role of cis-regulatory sequences in controlling genome integrity.

Project IDs

Project ID:PC10705-0096
External Project ID:MOST102-2320-B182-001-MY3
Effective start/end date01/08/1531/07/16


  • Somatic hypermutation
  • gene conversion
  • AID
  • DNA repair
  • mutagenesis
  • enhancers


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