Multiple transcription factor binding sites predict AID targeting in non-Ig genes

J Immunol. 2013 Apr 15;190(8):3878-88. doi: 10.4049/jimmunol.1202547. Epub 2013 Mar 20.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocyte Subsets / immunology
  • B-Lymphocyte Subsets / metabolism
  • Binding Sites / genetics
  • Binding Sites / immunology
  • Cytidine Deaminase / genetics
  • Cytidine Deaminase / metabolism*
  • E-Box Elements / genetics
  • Genes, Immunoglobulin
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Mice, Transgenic
  • Predictive Value of Tests
  • Somatic Hypermutation, Immunoglobulin*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • Transcription Factors
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase

Associated data

  • GEO/GSE44260