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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-? 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.

SUBMITTER: Duke JL

PROVIDER: S-EPMC3689293 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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

Duke Jamie L JL Liu Man M Yaari Gur G Khalil Ashraf M AM Tomayko Mary M MM Shlomchik Mark J MJ Schatz David G DG Kleinstein Steven H SH

Journal of immunology (Baltimore, Md. : 1950) 20130320 8

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 in ...[more]

PMID: 23514741

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Project description:This study was designed to test the idea that the regulatory regions of human genes have evolved to be resistant to the effects of mutations in their primary function, the control of gene expression. It is proposed that the transcription factor/transcription factor binding site (TF/TFBS) pair having the greatest effect on control of a gene is the one with the highest abundance among the regulatory elements. Other pairs would have the same effect on gene expression and would predominate in the event of a mutation in the most abundant pair. It is expected that the overall regulatory design proposed here will be highly resistant to mutagenic change that would otherwise affect expression of the gene. The idea was tested beginning with a database of 42 human genes highly specific for expression in brain. For each gene, the five most abundant TF/TFBS pairs were identified and compared in their TFBS occupancy as measured by their ChIP-seq signal. A similar signal was observed and interpreted as evidence that the TF/TFBS pairs can substitute for one another. TF/TFBS pairs were also compared in their ability to substitute for one another in their effect on the level of gene expression. The study of brain specific genes was complemented with the same analysis performed with 31 human liver specific genes. Like the study of brain genes, the liver results supported the view that TF/TFBS pairs in liver specific genes can substitute for one another in the event of mutagenic damage. Finally, the TFBSs in the brain specific and liver specific gene populations were compared with each other with the goal of identifying any brain selective or liver selective TFBSs. Of the 89 TFBSs in the pooled population, 58 were found only in brain specific but not liver specific genes, 8 only in liver specific but not brain specific genes and 23 were found in both brain and liver specific genes. The results were interpreted to emphasize the large number of TFBS in brain specific genes.

Dataset Information

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

Publications

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

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