title: Separation of mutational and transcriptional enhancers in Ig genes.
abstract: Secondary Ig gene diversification relies on activation-induced cytidine deaminase (AID) to create U:G mismatches that are subsequently fixed by mutagenic repair pathways. AID activity is focused to Ig loci by cis-regulatory DNA sequences named targeting elements. In this study, we show that in contrast to prevailing thought in the field, the targeting elements in the chicken IGL locus are distinct from classical transcriptional enhancers. These mutational enhancer elements (MEEs) are required over and above transcription to recruit AID-mediated mutagenesis to Ig loci. We identified a small 222-bp fragment in the chicken IGL locus that enhances mutagenesis without boosting transcription, and this sequence represents a key component of an MEE. Lastly, MEEs are evolutionarily conserved among birds, both in sequence and function, and contain several highly conserved sequence modules that are likely involved in recruiting trans-acting targeting factors. We propose that MEEs represent a novel class of cis-regulatory elements for which the function is to control genomic integrity.
authors.affiliation: Molecular Immunology Unit, Laboratory of Molecular Biology and Immunology, National Institute on Aging/National Institutes of Health, Biomedical Research Center, Baltimore, MD 21224, USA.
authors.forename: Naga Rama
authors.initials: NR
authors.lastname: Kothapalli
authors.forename: Kaitlin M
authors.initials: KM
authors.lastname: Collura
authors.forename: Darrell D
authors.initials: DD
authors.lastname: Norton
authors.forename: Sebastian D
authors.initials: SD
authors.lastname: Fugmann
mesh_terms: D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D015139:Blotting, Southern; D002478:Cells, Cultured; D002645:Chickens; D017124:Conserved Sequence; D003564:Cytidine Deaminase / Q000235:genetics / Q000276:immunology; D053843:DNA Mismatch Repair / Q000235:genetics* / Q000276:immunology; D004742:Enhancer Elements, Genetic / Q000235:genetics* / Q000276:immunology; D005803:Genes, Immunoglobulin / Q000235:genetics*; D007147:Immunoglobulin Light Chains / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D007147:Immunoglobulin Light Chains; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase