title: Multiple transcription factor binding sites predict AID targeting in non-Ig genes.
abstract: Aberrant targeting of the enzyme activation-induced cytidine deaminase (AID) results in the accumulation of somatic mutations in ≈ 25% of expressed genes in germinal center B cells. Observations in Ung(-/-) Msh2(-/-) mice suggest that many other genes efficiently repair AID-induced lesions, so that up to 45% of genes may actually be targeted by AID. It is important to understand the mechanisms that recruit AID to certain genes, because this mistargeting represents an important risk for genome instability. We hypothesize that several mechanisms combine to target AID to each locus. To resolve which mechanisms affect AID targeting, we analyzed 7.3 Mb of sequence data, along with the regulatory context, from 83 genes in Ung(-/-) Msh2(-/-) mice to identify common properties of AID targets. This analysis identifies three transcription factor binding sites (E-box motifs, along with YY1 and C/EBP-β binding sites) that may work together to recruit AID. Based on previous knowledge and these newly discovered features, a classification tree model was built to predict genome-wide AID targeting. Using this predictive model, we were able to identify a set of 101 high-interest genes that are likely targets of AID.
authors.affiliation: Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06511, USA.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Duke
authors.forename: Man
authors.initials: M
authors.lastname: Liu
authors.forename: Gur
authors.initials: G
authors.lastname: Yaari
authors.forename: Ashraf M
authors.initials: AM
authors.lastname: Khalil
authors.forename: Mary M
authors.initials: MM
authors.lastname: Tomayko
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Shlomchik
authors.forename: David G
authors.initials: DG
authors.lastname: Schatz
authors.forename: Steven H
authors.initials: SH
authors.lastname: Kleinstein
mesh_terms: D000818:Animals; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics / Q000276:immunology; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D024721:E-Box Elements / Q000235:genetics; D005803:Genes, Immunoglobulin; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011237:Predictive Value of Tests; D027041:Somatic Hypermutation, Immunoglobulin; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D014157:Transcription Factors; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase